Background

All studies of treatment-free remission (TFR) in patients with chronic myeloid leukaemia have discontinued tyrosine kinase inhibitor (TKI) treatment abruptly and have focussed on patients with stable MR4 (BCR-ABL to ABL ratio ≤0·01%). We aimed to examine the effects of gradual treatment withdrawal and whether TFR is feasible for patients with less deep but stable remission.

Methods

The De-Escalation and Stopping Treatment with Imatinib, Nilotinib, or sprYcel (DESTINY) study is a non-randomised, phase 2 trial undertaken at 20 UK hospitals. We recruited patients (aged ≥18 years) with chronic myeloid leukaemia in first chronic phase, who had received TKI therapy for 3 years or more, with three or more BCR-ABL quantitative PCR transcript measurements (BCR-ABL to ABL1 ratio) less than 0·1% (major molecular response [MMR]) in the 12 months before entry. Patients with all PCR measurements less than 0·01% were assigned to the MR4 group. Patients with results between 0·1% and 0·01% were allocated to the MMR group. TKI treatment was de-escalated to half the standard dose for 12 months, then stopped for a further 24 months, with frequent PCR monitoring. Recurrence was defined as the first of two consecutive samples with PCR measurement greater than 0·1%, which required treatment recommencement at full dose. The primary endpoint was the proportion of patients who could first de-escalate their treatment for 12 months, and then stop treatment completely for a further 2 years, without losing MMR. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01804985.

Findings

Treatment at entry was imatinib (n=148), nilotinib (n=16), or dasatinib (n=10), for a median of 6·9 years (IQR 4·8–10·2). Between Dec 16, 2013, and May 6, 2015, we enrolled 49 patients into the MMR group and 125 into the MR4 group. In the MR4 group, 84 (67%) patients reached the 36-month trial completion point and recurrence-free survival was 72% (95% CI 64–80). In the MMR group, 16 (33%) entrants completed the study and recurrence-free survival was 36% (25–53). No disease progression was seen and two deaths occurred due to unrelated causes. All recurrences regained MMR within 5 months of treatment resumption.

Interpretation

Initial de-escalation before discontinuation might improve the success of TFR protocols, although the mechanism of its benefit is not yet clear. The findings also suggest that TFR merits further study in patients with stable MMR.

Funding

Newcastle University and Bloodwise.

中文翻译：

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慢性粒细胞白血病患者完全停止治疗前酪氨酸激酶抑制剂治疗的降级（DESTINY）：一项非随机、2 期试验

背景

所有慢性粒细胞白血病患者的无治疗缓解（TFR）研究均突然停止酪氨酸激酶抑制剂（TKI）治疗，并重点关注MR4稳定（BCR-ABL与ABL比值≤0·01% ）的患者。我们的目的是研究逐渐停止治疗的效果以及 TFR 对于缓解程度不深但稳定的患者是否可行。

方法

使用伊马替尼、尼洛替尼或 sprYcel 降级和停止治疗 (DESTINY) 研究是一项在 20 家英国医院进行的非随机 2 期试验。我们招募了慢性粒细胞白血病第一慢性期患者（年龄≥18岁），接受TKI治疗3年或以上，且3项或以上BCR-ABL定量PCR转录本测量值（BCR- ABL与ABL1比值）小于入组前 12 个月内为 0·1%（主要分子反应 [MMR]）。所有 PCR 测量值均小于 0·01% 的患者被分配至 MR4 组。结果介于 0·1% 和 0·01% 之间的患者被分配到 MMR 组。TKI 治疗逐渐减至标准剂量的一半，持续 12 个月，然后再停止 24 个月，并进行频繁的 PCR 监测。复发被定义为PCR测量值大于0·1%的两个连续样本中的第一个，这需要以全剂量重新开始治疗。主要终点是能够首先在 12 个月内逐步降级治疗，然后再完全停止治疗 2 年而不失去 MMR 的患者比例。分析是按意向治疗进行的。本研究已在 ClinicalTrials.gov 注册，编号为 NCT01804985。

发现

入组时的治疗为伊马替尼 (n=148)、尼洛替尼 (n=16) 或达沙替尼 (n=10)，中位治疗时间为 6·9 年 (IQR 4·8–10·2)。2013年12月16日至2015年5月6日期间，我们将49名患者纳入MMR组，将125名患者纳入MR4组。在 MR4 组中，84 名 (67%) 患者达到了 36 个月的试验完成点，无复发生存率为 72% (95% CI 64-80)。在 MMR 组中，16 名 (33%) 参与者完成了研究，无复发生存率为 36% (25-53)。没有看到疾病进展，并且有两人因不相关的原因死亡。所有复发均在恢复治疗后 5 个月内恢复 MMR。

解释

停药前的初步降级可能会提高 TFR 方案的成功率，尽管其益处机制尚不清楚。研究结果还表明，对于 MMR 稳定的患者，TFR 值得进一步研究。

资金

纽卡斯尔大学和 Bloodwise。