Olivieri A, Mancini G, Olivieri J, Marinelli Busilacchi E, Cimminiello M, Pascale S P, Nuccorini R, Patriarca F, Corradini P, Bacigalupo A, Angelini S, Poloni A, Grillo G, Onida F, Martino M, Di Renzo N, Nagler A, Mordini N, Bruno B, Ciceri F, Bonifazi F
Unit of Hematology, AUO Ospedali Riuniti di Ancona, Ancona, Italy.
Department of Clinical and Molecular Science, Università Politecnica delle Marche, Ancona, Italy.
Bone Marrow Transplant. 2020 Nov;55(11):2077-2086. doi: 10.1038/s41409-020-0902-9. Epub 2020 Apr 24.
We conducted a phase I-II study to evaluate Nilotinib (NIL) safety and pharmacokinetics in 22 SR-cGVHD patients; we also evaluated ORR by using in parallel NIH criteria and an exploratory approach, combining objective improvement (OI) without failure criteria (GITMO criteria). Results: 22 patients were enrolled. After dose escalation up to 600 mg/day, MTD was not reached. Main toxicities were asthenia, headache, nausea, pruritus, cramps, and mild anemia. Mean and median plasma concentrations of NIL (C-NIL) were 817 (SD ± 450) and 773 ng/ml. ORR at 6 months, according to 2005 and 2014 NIH and GITMO criteria were 27.8%, 22.2%, and 55.6% respectively; close correspondence has been observed for ORR, according to 2014 NIH criteria, both assessed in a conventional way and assisted by dedicated software (CROSY). At 48 months OS was 75% while FFS, according to NIH and GITMO criteria, was 30 and 25%. In conclusion the safety profile of NIL and long-term outcome makes NIL an attractive option in SR-cGVHD. Exploratory GITMO criteria could represent an alternative tool for easy response evaluation in patients with prevalent skin and lung involvement, but require validation in a larger population; CROSY software showed excellent reliability in capturing ORR according to the 2014 NIH criteria.
我们开展了一项I-II期研究，以评估尼洛替尼（NIL）在22例类固醇难治性慢性移植物抗宿主病（SR-cGVHD）患者中的安全性和药代动力学；我们还通过并行使用美国国立卫生研究院（NIH）标准和一种探索性方法（结合无失败标准的客观改善（OI），即全球移植物抗宿主病国际组织（GITMO）标准）来评估客观缓解率（ORR）。结果：入组22例患者。剂量递增至600mg/天仍未达到最大耐受剂量（MTD）。主要毒性为乏力、头痛、恶心、瘙痒、痉挛和轻度贫血。NIL的平均血浆浓度和中位数血浆浓度（C-NIL）分别为817（标准差±450）和773ng/ml。根据2005年和2014年NIH及GITMO标准，6个月时的ORR分别为27.8%、22.2%和55.6%；根据2014年NIH标准评估的ORR，无论是以传统方式评估还是借助专用软件（CROSY）辅助评估，均观察到密切的一致性。48个月时总生存期（OS）为75%，而根据NIH和GITMO标准，无进展生存期（FFS）分别为30%和25%。总之，NIL的安全性概况和长期疗效使NIL成为SR-cGVHD中一个有吸引力的选择。探索性的GITMO标准可能是在皮肤和肺部受累为主的患者中进行简易反应评估的替代工具，但需要在更大规模人群中进行验证；CROSY软件在根据2014年NIH标准捕获ORR方面显示出出色的可靠性。
