University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio.
Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Biol Blood Marrow Transplant. 2018 Oct;24(10):2017-2024. doi: 10.1016/j.bbmt.2018.06.016. Epub 2018 Jun 20.
Relapse is the main cause of treatment failure after allogeneic stem cell transplant (alloSCT) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Injectable azacitidine can improve post-transplant outcomes but presents challenges with exposure and compliance. Oral CC-486 allows extended dosing to prolong azacitidine activity. We investigated use of CC-486 maintenance therapy after alloSCT. Adults with MDS or AML in morphologic complete remission at CC-486 initiation (42 to 84 days after alloSCT) were included. Patients received 1 of 4 CC-486 dosing schedules per 28-day cycle for up to 12 cycles. Endpoints included safety, pharmacokinetics, graft-versus-host disease (GVHD) incidence, relapse/progression rate, and survival. Of 30 patients, 7 received CC-486 once daily for 7 days per cycle (200 mg, n = 3; 300 mg, n = 4) and 23 for 14 days per cycle (150 mg, n = 4; 200 mg, n = 19 [expansion cohort]). Grades 3 to 4 adverse events were infrequent and occurred with similar frequency across regimens. Standard concomitant medications did not alter CC-486 pharmacokinetic parameters. Three patients (10%) experienced grade III acute GVHD and 9 experienced chronic GVHD. Of 28 evaluable patients, 6 (21%) relapsed or had progressive disease: 3 of 7 patients (43%) who had received 7-day dosing and 3 of 23 (13%) who had received 14-day dosing. Transplant-related mortality was 3%. At 19 months of follow-up, median overall survival was not reached. Estimated 1-year survival rates were 86% and 81% in the 7-day and 14-day dosing cohorts, respectively. CC-486 maintenance was generally well tolerated, with low rates of relapse, disease progression, and GVHD. CC-486 maintenance may permit epigenetic manipulation of the alloreactive response postallograft. Findings require confirmation in randomized trials. (ClinicalTrials.gov NCT01835587.).
在急性髓系白血病（AML）和骨髓增生异常综合征（MDS）患者接受异基因造血干细胞移植（alloSCT）后，复发是导致治疗失败的主要原因。注射用阿扎胞苷可改善移植后的疗效，但在暴露度和依从性方面存在挑战。口服 CC-486 可延长给药时间以延长阿扎胞苷的活性。我们研究了 alloSCT 后 CC-486 维持治疗的应用。在 CC-486 起始时（alloSCT 后 42 至 84 天）处于形态学完全缓解的 MDS 或 AML 成人患者被纳入研究。患者接受每 28 天周期的 4 种 CC-486 给药方案中的 1 种，最多 12 个周期。主要终点包括安全性、药代动力学、移植物抗宿主病（GVHD）发生率、复发/进展率和生存率。30 例患者中，7 例患者每周期接受 7 天 CC-486 治疗（200mg，n=3；300mg，n=4），23 例患者每周期接受 14 天 CC-486 治疗（150mg，n=4；200mg，n=19[扩展队列]）。3 至 4 级不良事件少见，且各方案的发生频率相似。标准伴随药物不会改变 CC-486 的药代动力学参数。3 例患者（10%）发生 3 级急性 GVHD，9 例发生慢性 GVHD。28 例可评估患者中，6 例（21%）复发或疾病进展：7 天方案组 3 例（43%），14 天方案组 3 例（13%）。移植相关死亡率为 3%。随访 19 个月时，中位总生存期尚未达到。7 天和 14 天方案组的 1 年生存率估计分别为 86%和 81%。CC-486 维持治疗耐受性良好，复发、疾病进展和 GVHD 发生率低。CC-486 维持治疗可能允许对移植后同种异体反应进行表观遗传操作。这些发现需要在随机试验中得到证实。（ClinicalTrials.gov NCT01835587）。
