[ASH2016]Glasdegib+低剂量阿糖胞苷可改善AML或高危MDS的生存期
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今日，第58届美国血液学年会（ASH，12月3日~6日）于美国圣地亚哥召开。其间，在“急性髓系白血病：新疗法，不包括移植”专场上，一项口头报告表明glasdegib联合低剂量阿糖胞苷要比单独应用阿糖胞苷更能改善急性髓系白血病或高危骨髓增生异常综合征患者的总生存期（OS）。研究详情如下：
背景
Hedgehog信号通路（HhP）在白血病和骨髓增生异常综合征（MDS）中异常活化，维持了癌症干细胞的自我更新能力。HhP抑制能够减少白血病干细胞。Glasdegibis是一种强效选择性的口服HhP抑制剂，在临床前试验和临床试验中表现出治疗活性。Glasdegibto标准化疗看似对MDS和急性髓系白血病（AML）具有临床活性，产生的毒性作用也可以接受。
方法
该项研究（NCT01546038）纳入了先前未经治的AML或不适宜强化化疗的MDS患者，按照2：1将其随机分配至低剂量阿糖胞苷（LDAC；20 mg，2次/d，持续10天；皮下注射；周期为q28天）+ glasdegib（100mg，1次/d；口服）治疗组或单独LDAC治疗组。主要终点是总生存率（OS）。完成招募和至少产生92个总生存事件时进行最终分析。
结果
共纳入132名患者，其中AML 116名， MDS 16名。研究人员将受试者随机分配至LDAC + glasdegib组（n = 88） 和LDAC 单药治疗组（n = 44）。两组患者中位年龄、基线细胞遗传学风险和诊断的人口统计和基线特征几乎一致。84名患者接受了LDAC + glasdegib 治疗，41名患者接受了LDAC单药治疗（对7名随机化或未接受治疗的患者进行生存期随访）。LDAC + glasdegib组和LDAC单药组的中位治疗持续期分别为83天和47天，中位随访期分别为14.3个月和12.4个月。
联合治疗组中，12名患者继续接受治疗，25名患者接受了随访；单药组中，1名患者继续治疗，5名患者接受了随访。联合治疗组中更常见的不良反应是血细胞减少和胃肠道反应，Hh相关性不良反应有味觉障碍、肌肉痉挛和脱发，发热性中性粒细胞减少症在该组中也更常见，但脓毒症发病率更低，肺炎发病率相似。两组患者最常见的致死原因是疾病进展。2~4级QTcF延长在单药组中更常见。
从数据上看，联合组的完全缓解率要高于单药组，分别为15% vs 2.3%。。根据意向治疗人群的96个生存事件分析结果，联合组和单药组的中位OS（mOS）分别为8.3 vs 4.9个月；对于良好/中间级风险的患者，mOS分别为12.2 vs 6.0个月；对于不良风险的患者， mOS分别为.4 vs 2.3个月；对于AML患者，mOS分别为8.3 vs 4.3个月。
结论
对于AML和高危MDS患者而言，glasdegib联合低剂量阿糖胞苷要比单独应用阿糖胞苷更能改善OS，这种OS改善可见于各种亚组，尤其是良好/中间级风险的患者。这种联合方案产生的毒性反应液易于接受。因此，glasdegib添加至低剂量阿糖胞苷治疗中将有可能成为AML或高危MDS患者的治疗方案选择。
摘要详情
A Phase 2 Randomized Study of Low Dose Ara-C with or without Glasdegib (PF-04449913) in Untreated Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome
Background: The Hedgehog signaling pathway (HhP) is aberrantly activated in leukemias and myelodysplastic syndrome (MDS), promoting cancer stem cell maintenance. HhP inhibition reduces leukemic stem cells. Glasdegib is a potent, selective, oral HhP inhibitor, with activity in pre-clinical and clinical studies. The addition of glasdegib to standard chemotherapy (CT) has an acceptable safety profile and appears to have clinical activity in MDS and acute myeloid leukemia (AML).
Methods: In this study (NCT01546038), previously untreated AML or high-risk MDS patients (pts) ineligible for intensive CT were randomized 2:1 to receive low-dose cytarabine (LDAC) 20 mg subcutaneously twice a day x 10 days q28 days + oral glasdegib 100 mg daily or LDAC alone for as long as pts received clinical benefit. The primary endpoint was overall survival (OS). The final analysis was conducted after completion of recruitment (Oct 2015) and at least 92 OS events.
Results: As of Apr 2016, 132 pts (116 AML, 16 MDS) were randomized to LDAC + glasdegib (n = 88) or LDAC alone (n = 44) (stratified as good/intermediate [int.] vs poor risk) (Table). Demographic and baseline characteristics were similar between arms in median age, baseline cytogenetic risk, and diagnosis. Eighty-four pts received LDAC + glasdegib and 41 pts LDAC alone (7 randomized/not treated pts were followed for survival). Median treatment duration was 83 days for LDAC + glasdegib and 47 days for LDAC alone; median follow up was 14.3 months and 12.4 months, respectively. In the glasdegib arm, 12 pts were continuing treatment and 25 were in follow up; in the LDAC arm, 1 pt was on treatment and 5 in follow up. Cytopenias and gastrointestinal toxicities were the adverse events (AEs) occurring more frequently in the LDAC + glasdegib arm. Hh-associated AEs in the glasdegib arm included dysgeusia (23.8%), muscle spasms (20.2%) and alopecia (10.7%). Serious AEs of febrile neutropenia were more frequent in the glasdegib arm, but sepsis rates were lower and pneumonia rates were similar. The most common cause of death was disease progression in both arms. Grade 2-4 QTcF prolongation was more frequent in the LDAC arm.
Investigator-reported complete response (CR) rates were numerically higher for LDAC + glasdegib (n = 17, 15%) vs LDAC alone (n = 1, 2.3%), p-value 0.0142. Based on intent to treat analysis of 96 events, median OS (mOS) for LDAC + glasdegib was 8.3 (80% confidence interval [CI] 6.9, 9.9) vs 4.9 months (80% CI 3.5, 6.0) for LDAC alone (HR 0.511, 80% CI 0.386, 0.675; one-sided log rank p-value 0.0020 stratified by cytogenetic risk). For good/int. risk, mOS for LDAC + glasdegib was 12.2 vs 6.0 months for LDAC alone (HR 0.464, p-value 0.0035). For poor risk, mOS for LDAC + glasdegib was 4.4 vs 2.3 months (HR 0.575, p-value 0.0422). In AML pts, mOS for LDAC + glasdegib was 8.3 vs 4.3 months for LDAC alone (HR 0.462, p-value 0.0004).
Conclusions: The addition of glasdegib to LDAC for AML and high-risk MDS pts improved OS compared with LDAC alone. The improvement was consistent among subgroups, particularly in good/int. risk pts. Treatment was associated with an acceptable safety profile. The addition of glasdegib to LDAC may be a treatment option for pts with AML or high-risk MDS.
研究中的重要结果
