Knight Cancer Institute, Oregon Health & Science University, Portland, OR.
Division of Hematology, Department of Medicine, Stanford University School of Medicine/Stanford Cancer Institute, Stanford, CA.
J Clin Oncol. 2020 Apr 1;38(10):1006-1018. doi: 10.1200/JCO.19.00895. Epub 2019 Dec 27.
Colony-stimulating factor-3 receptor ()-T618I is a recurrent activating mutation in chronic neutrophilic leukemia (CNL) and to a lesser extent in atypical chronic myeloid leukemia (aCML) resulting in constitutive JAK-STAT signaling. We sought to evaluate safety and efficacy of the JAK1/2 inhibitor ruxolitinib in patients with CNL and aCML, irrespective of mutation status.
We conducted a phase II study of ruxolitinib in 44 patients (21 CNL and 23 aCML). The primary end point was overall hematologic response rate (ORR) by the end of 6 continuous 28-day cycles for the first 25 patients enrolled. We considered a response as either partial (PR) or complete response (CR). We expanded accrual to 44 patients to increase our ability to evaluate secondary end points, including grade ≥ 3 adverse events, spleen volume, symptom assessment, genetic correlates of response, and 2-year survival.
ORR was 32% for the first 25 enrolled patients (8 PR [7 CNL and 1 aCML]). In the larger cohort of 44 patients, 35% had a response (11 PR [9 CNL and 2 aCML] and 4 CR [CNL]), and 50% had oncogenic mutations. The mean absolute allele burden reduction of -T618I after 6 cycles was greatest in the CR group, compared with the PR and no response groups. The most common cause of death is due to disease progression. Grade ≥ 3 anemia and thrombocytopenia were observed in 34% and 14% of patients, respectively. No serious adverse events attributed to ruxolitinib were observed.
Ruxolitinib was well tolerated and demonstrated an estimated response rate of 32%. Patients with a diagnosis of CNL and/or harboring -T618I were most likely to respond.
集落刺激因子-3 受体（）-T618I 是慢性中性粒细胞白血病（CNL）的复发性激活突变，在非典型慢性髓性白血病（aCML）中则较少见，导致组成性 JAK-STAT 信号转导。我们试图评估 JAK1/2 抑制剂鲁索利替尼在 CNL 和 aCML 患者中的安全性和疗效，而不论突变状态如何。
我们对 44 例患者（21 例 CNL 和 23 例 aCML）进行了鲁索利替尼的 II 期研究。主要终点是前 25 例入组患者连续 6 个 28 天周期结束时的总体血液学反应率（ORR）。我们将反应定义为部分（PR）或完全反应（CR）。我们将入组人数扩大到 44 例，以提高我们评估次要终点的能力，包括≥3 级不良事件、脾脏体积、症状评估、反应的遗传相关性和 2 年生存率。
前 25 例入组患者的 ORR 为 32%（8 例 PR[7 例 CNL 和 1 例 aCML]）。在 44 例较大的患者队列中，35%的患者有反应（11 例 PR[9 例 CNL 和 2 例 aCML]和 4 例 CR[CNL]），50%的患者有致癌性突变。与 PR 和无反应组相比，CR 组在 6 个周期后-T618I 的绝对等位基因负荷减少最大。最常见的死亡原因是疾病进展。分别有 34%和 14%的患者出现 3 级或以上贫血和血小板减少。未观察到与鲁索利替尼相关的严重不良事件。
鲁索利替尼耐受性良好，估计反应率为 32%。诊断为 CNL 和/或携带-T618I 的患者最有可能有反应。
