Department of Hematology, Iwate Prefectural Central Hospital, Morioka, Japan.
Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.
Lancet Haematol. 2021 Dec;8(12):e902-e911. doi: 10.1016/S2352-3026(21)00333-1.
BCR-ABL1 tyrosine kinase inhibitors (TKIs) are commonly initiated in older patients with chronic myeloid leukaemia in the chronic phase at standard doses. However, because of their safety profile in this population, appropriate therapy has not been established. We aimed to investigate whether a lower than standard dose of dasatinib was an appropriate therapy for older patients with chronic myeloid leukaemia in the chronic phase.
DAsatinib, Very Low-dose, for Elderly CML-CP patients (DAVLEC) was a multicentre, single-arm, phase 2 trial done in 25 Japanese hospitals. We enrolled patients older than 70 years with newly diagnosed chronic myeloid leukaemia in the chronic phase, ECOG performance status 0-2, and no previous treatment for CML other than hydroxyurea within 4 weeks. Second-generation TKI dasatinib was given orally at a starting dose of 20% of the standard dose (20 mg/day). If the treatment was assessed as optimal response at 3 months, 6 months, and 9 months and adverse events were grade 2 or better (according to the NCI Common Toxicity Criteria v 4.0), the same dose was continued. If response was suboptimal and adverse events were grade 2 or better, the dose was increased by 20 mg/day. Once a dose reduction had been made because of a grade 3 or worse adverse event, there were no further dose increases. Treatment was discontinued if assessed as failure (disease progression to the accelerated phase or acute phase). The primary endpoint was the achievement of major molecular response at 12 months, assessed using a per-protocol analysis. This trial is registered at with the UMIN clinical trial registry, UMIN000024548, and has completed its planned observation period.
Between Nov 1, 2016, and Oct 30, 2019, 52 patients received first-line dasatinib therapy at 20 mg/day. The median age at diagnosis was 77·5 years (73·5-83·0). 35 (67%) patients were male and 17 (33%) were female. 31 (60%) of 52 patients reached major molecular response at 12 months (one-sided 95% CI 48-71), with a median follow-up of 366 days (IQR 353-372). Grade 3-4 adverse events were reported in 12 (23%) patients. Neutropenia was the most frequent grade 3-4 adverse event, occurring in three (6%) patients. No treatment-related deaths were observed.
Low-dose dasatinib at 20mg/day is worthy of consideration as a starting dose for older patients with newly diagnosed chronic myeloid leukaemia in the chronic phase. However, this dose needs to be further studied in a larger cohort and with a more ethnically diverse population.
Bristol-Myers Squibb.
BCR-ABL1 酪氨酸激酶抑制剂（TKIs）通常在慢性期的老年慢性髓性白血病患者中以标准剂量起始使用。然而，由于其在该人群中的安全性特征，尚未确定合适的治疗方法。我们旨在研究低于标准剂量的达沙替尼是否是慢性期老年慢性髓性白血病患者的合适治疗方法。
达沙替尼、低剂量、老年 CML-CP 患者（DAVLEC）是一项在 25 家日本医院进行的多中心、单臂、2 期试验。我们招募了年龄大于 70 岁、新诊断为慢性期慢性髓性白血病、ECOG 体能状态 0-2 分、且在 4 周内未接受除羟基脲以外的其他 CML 治疗的患者。第二代 TKI 达沙替尼以标准剂量的 20%（20mg/天）起始口服给药。如果在 3 个月、6 个月和 9 个月时评估治疗为最佳反应，且不良事件为 2 级或更高（根据 NCI 常见毒性标准 v 4.0），则继续使用相同剂量。如果反应不理想且不良事件为 2 级或更高，则将剂量增加 20mg/天。一旦因 3 级或更高级别的不良事件而降低剂量，则不再增加剂量。如果评估为治疗失败（疾病进展为加速期或急变期），则停止治疗。主要终点是通过方案分析评估的 12 个月时达到主要分子缓解。该试验在 UMIN 临床试验注册处（UMIN000024548）注册，已完成计划的观察期。
2016 年 11 月 1 日至 2019 年 10 月 30 日，52 例患者接受了达沙替尼 20mg/天的一线治疗。诊断时的中位年龄为 77.5 岁（73.5-83.0）。35 例（67%）患者为男性，17 例（33%）为女性。52 例患者中有 31 例（60%）在 12 个月时达到主要分子缓解（单侧 95%CI 48-71），中位随访时间为 366 天（IQR 353-372）。12 例（23%）患者报告了 3-4 级不良事件。中性粒细胞减少症是最常见的 3-4 级不良事件，发生在 3 例（6%）患者中。未观察到与治疗相关的死亡。
达沙替尼低剂量 20mg/天可作为新诊断的慢性期老年慢性髓性白血病患者的起始剂量。然而，该剂量需要在更大的队列和更多种族多样化的人群中进一步研究。
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