髓系肿瘤（骨髓增生异常综合征[MDS]、骨髓纤维化和慢性髓细胞/单核细胞[CMML]）是侵袭性血液恶性肿瘤，尽管近期已经获得批准，仍需要新的治疗方法以改善治疗效果。刺猬通路（HH）是癌干细胞生存的主要通路之一，且多种HH抑制剂（HHi）已在临床实践中获得批准。Sonidegib（SON）为一种口服HHi，该Phase 1/1b试验测试了其与新诊断和复发/难治的慢性MN或急性髓性白血病（AML）患者中的azacitidine（AZA，75 mg/m2每7天）的联合应用。本研究共治疗了62名患者（28名[45％]为新诊断），其中10名患者接受了剂量寻找阶段的治疗，52名患者接受了Phase 1b阶段的治疗。SON每个周期口服200 mg每天，经认定为Phase 1b的推荐剂量。在21名复发/难治AML患者中，有2名患者获得了反应（1个完全缓解/1个形态学无白血病状态），而在7名复发/难治MDS /CMML患者中，未见到响应。在新诊断AML/MDS中，27名患者中有6名患者获得了反应（其中3名完全缓解，2名形态学无白血病状态）。新诊断MDS和AML的中位生存期分别为26.4个月和4.7个月。副作用方面，疲劳、便秘、恶心、咳嗽、失眠和腹泻等常见副作用占比超过20％，安全性令人满意。研究中只有7％的患者死亡，且没有死亡被认为与治疗相关。我们的研究表明，AZA + SON是一种在MN患者中安全的联合治疗方案。与其他刺猬通路抑制剂类似，该联合应用在髓系肿瘤患者中的反应率有限。©2023年美国癌症协会。

Myeloid neoplasms (myelodysplastic syndrome [MDS], myelofibrosis, and chronic myelomonocytic [CMML]) are aggressive hematological malignancies for which, despite recent approvals, novel therapies are needed to improve clinical outcomes. The hedgehog (HH) pathway is one of the main pathways for cancer stem cells survival and several HH inhibitors (HHi) are approved in clinical practice.Sonidegib (SON), an oral HHi, was tested in this phase 1/1b trial in combination with azacitidine (AZA, 75 mg/m2 days ×7) in patients with newly diagnosed and relapsed/refractory (r/r) chronic MN or acute myeloid leukemia (AML).Sixty-two patients (28 [45%] newly diagnosed) were treated in this study, including 10 patients in the dose-finding component and 52 patients in phase 1b. SON 200 mg oral daily on days 1-28 each cycle was deemed the recommended dose for phase 1b. Out of 21 rrAML patients, two achieved response (one complete response/one morphologic leukemia-free state) with no responses seen in seven r/r MDS/CMML patients. In newly diagnosed AML/MDS, response was seen in six (three had complete remission, two had morphological leukemia-free status) of 27 patients. Median overall survival was 26.4 and 4.7 months for newly diagnosed MDS and AML, respectively. Safety was satisfactory with common (>20%) side effects including fatigue, constipation, nausea, cough, insomnia, and diarrhea. Only 7% of patients died in the study, and none of the deaths were deemed related to treatment.Our study shows that AZA + SON are a safe combination in a patient with MN. Similar to other hedgehog inhibitors, this combination yielded limited response rate in patients with myeloid neoplasms.© 2023 American Cancer Society.