A phase I trial of palbociclib plus bortezomib in previously treated mantle cell lymphoma
A phase I trial of palbociclib plus bortezomib in previously treated mantle cell lymphoma
复制标题
DOI：
10.1080/10428194.2019.1612062
复制
发表时间：
2019-05-22
影响因子：
2.6
通讯作者：
Leonard, John P.
中科院分区：
文献类型：
--
作者：
Martin, Peter;Ruan, Jia;Leonard, John P.
在套细胞淋巴瘤（MCL）中，细胞周期蛋白D1与CDK 4/6结合磷酸化Rb，释放G1至S期细胞周期的断裂。Palbociclib是一种特异性、强效、口服的CDK 4/6抑制剂，能够诱导Rb+ MCL细胞完全、延长G1期细胞周期停滞（pG 1）。蛋白酶体抑制剂硼替佐米被美国食品和药物管理局批准用于治疗套细胞淋巴瘤。Palbociclib诱导的pG 1似乎使MCL细胞对低剂量硼替佐米的杀伤敏感，可能改善其活性和耐受性。我们在既往接受过治疗的MCL患者中开展了一项palbociclib + bortez的I期试验（NCT 01111188）。患者在每个21天周期的第1-12天接受palbociclib 75 mg（剂量水平1）、100 mg（剂量水平2）或125 mg（剂量水平3和4）治疗，此外还在第8、11、15和18天静脉注射硼替佐米1.0 mg/m2（剂量水平1、2、3）或1.3 mg/m2（剂量水平4）。共入组了19例患者，中位年龄为64岁，平均接受过2种既往治疗。2例受试者发生剂量限制性毒性（DLT）：血小板减少症（剂量水平1）和中性粒细胞减少症（剂量水平3）。尽管在剂量水平4未观察到DLT，但由于血细胞减少，所有患者在第2周期均需要延迟给药，研究小组决定停止试验。19例患者中有4例达到临床缓解，包括1例完全缓解。3例患者接受治疗超过1年，其中1例患者接受Palbociclib单药治疗超过6年。Palbociclib 125 mg（第1-12天）联合硼替佐米1.0 mg/m2（第8、11、15和18天）治疗既往接受过治疗的MCL是可行和有效的，主要毒性是骨髓抑制。该方案可能是值得进一步评估的非胚样MCL患者后，其他新的药物失败。
In mantle cell lymphoma (MCL), cyclin D1 combines with CDK4/6 to phosphorylate Rb, releasing a break on the G1 to S phase cell cycle. Palbociclib is a specific, potent, oral inhibitor of CDK4/6 capable of inducing a complete, prolonged G1 cell cycle arrest (pG1) in Rb+ MCL cells. The proteasome inhibitor bortezomib is approved by the US Food and Drug Administration for treatment of mantle cell lymphoma. Palbociclib-induced pG1 appears to sensitize MCL cells to killing by low-dose bortezomib, potentially improving its activity and tolerability. We conducted a phase 1 trial of palbociclib plus bortezomib in patients with previously treated MCL (NCT01111188). Patients received palbociclib at 75 mg (dose level 1), 100 mg (dose level 2), or 125 mg (dose levels 3 and 4) on days 1-12 of each 21-day cycle in addition to intravenous bortezomib 1.0 mg/m(2) (dose levels 1, 2, 3) or 1.3 mg/m(2) (dose level 4) on days 8, 11, 15 and 18. A total of 19 patients with a median age of 64 and an average of 2 prior therapies were enrolled. Two subjects experienced dose limiting toxicity (DLT): thrombocytopenia (dose level 1) and neutropenia (dose level 3). Although no DLTs were seen at dose level 4, all patients required dose delays during cycle 2 due to cytopenias, and the study team decided to stop the trial. Four of 19 patients achieved a clinical response, including one patient with a complete response. Three patients received treatment for more than one year, including one patient receiving single-agent palbociclib for more than 6 years. The combination of palbociclib 125 mg on days 1-12 plus bortezomib 1.0 mg/m(2) on days 8, 11, 15, and 18 of a 21-day cycle is feasible and active in previously treated MCL, with the primary toxicity being myelosuppression. The regimen may be worthy of further evaluation in patients with non-blastoid MCL following failure of other newer agents.