The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 401 N. Broadway room 1363, Baltimore, MD, 21287, USA.
Cancer Chemother Pharmacol. 2018 Feb;81(2):347-354. doi: 10.1007/s00280-017-3499-y. Epub 2017 Dec 13.
Everolimus, an mTOR inhibitor, is active in refractory lymphomas. However, toxicity with flat dosing limits its usage. Speculatively, pharmacokinetically-targeted dosing could improve tolerability. Therefore, we studied serum-trough dosing with rituximab as maintenance after high-dose cyclophosphamide (HDC) consolidation in lymphoma patients.
PATIENTS/METHODS: After HDC, everolimus was dosed to serum trough levels (goal 3-15 ng/mL), with quarterly rituximab infusions for 1 year while maintaining < grade II non-hematologic and < grade III hematologic toxicities. Adult patients in first PR/CR with: mantle cell, transformed, double-hit, or high risk chronic lymphocytic leukemia or in second PR for any relapsed B cell lymphoma were eligible. Prophylaxis was given for encapsulated organisms, HSV and PCP. Serum IgG levels were maintained > 500 mg/dL.
49 patients, median age: 59.0 years enrolled; MCL (26), CLL (10), transformed lymphoma (7), and other histologies (6). During the life of the study, the most frequent everolimus dosing has been 2.5 mg daily or 2.5 mg every other day; at these doses, serum levels are within the therapeutic range and non-hematologic toxicity is rare. At a median follow-up of 27.1 months, three patients remain on active therapy. Two patients withdrew secondary to potentially-attributable adverse events including a bacterial pneumonia and a viral pneumonia; this low rate of discontinuation compares well to other long-term everolimus trials. While a 58 and 76% EFS at 30 months for the entire cohort and MCL cohort, respectively, compares similarly to previously published HDC/rituximab data, longer follow-up is required.
Pharmacokinetically-targeted dosing appears to increase everolimus tolerability. This finding may be applicable to other patient populations.
依维莫司是一种 mTOR 抑制剂，在难治性淋巴瘤中具有活性。然而，由于平剂量毒性限制了其应用。推测，药代动力学靶向剂量可能会提高耐受性。因此，我们研究了在淋巴瘤患者中，高剂量环磷酰胺（HDC）巩固治疗后，使用利妥昔单抗作为维持治疗的血清谷浓度给药。
患者/方法：在 HDC 后，依维莫司的剂量设定为血清谷浓度（目标 3-15ng/mL），每季度给予利妥昔单抗输注 1 年，同时保持<Ⅱ级非血液学毒性和<Ⅲ级血液学毒性。符合以下条件的初治 PR/CR 成年患者（套细胞、转化、双打击或高风险慢性淋巴细胞白血病）或任何复发性 B 细胞淋巴瘤的二次 PR 患者有资格入组：有包膜的生物体、HSV 和 PCP 的预防。血清 IgG 水平维持>500mg/dL。
49 例患者，中位年龄为 59.0 岁，入组；MCL（26 例）、CLL（10 例）、转化性淋巴瘤（7 例）和其他组织学（6 例）。在研究期间，最常使用的依维莫司剂量是 2.5mg 每日或 2.5mg 隔日；在这些剂量下，血清水平处于治疗范围内，且非血液学毒性罕见。在中位随访 27.1 个月时，有 3 例患者仍在接受治疗。有 2 例患者因可能与药物相关的不良事件而退出研究，包括细菌性肺炎和病毒性肺炎；这种低停药率与其他长期依维莫司试验相当。在整个队列和 MCL 队列中，30 个月时的 EFS 分别为 58%和 76%，与先前发表的 HDC/利妥昔单抗数据相似，但需要更长时间的随访。
药代动力学靶向剂量似乎增加了依维莫司的耐受性。这一发现可能适用于其他患者群体。
