Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma
Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma
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DOI：
10.1182/blood-2018-09-875732
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发表时间：
2019-01-31
期刊：
影响因子：
20.3
通讯作者：
Mellinghoff, Ingo K.
中科院分区：
文献类型：
--
作者：
Grommes, Christian;Tang, Sarah S.;Mellinghoff, Ingo K.
伊布替尼是一类布鲁顿酪氨酸激酶（BTK）抑制剂，在复发性/难治性中枢神经系统（CNS）淋巴瘤中显示出单药活性。临床反应通常是短暂的或不完全的，这表明需要联合治疗方法。我们进行了一项1b期临床试验，以探索依西替尼（每日560或840 mg给药）与高剂量甲氨蝶呤（HD-MTX）和利妥昔单抗序贯联合治疗CNS淋巴瘤（CNSL）患者。HD-MTX剂量为3.5 g/m2，每2周一次，共8次（4个周期; 1个周期5 - 28天）。在HD-MTX输注当天暂停伊曲替尼，并在HD-MTX输注后5天或HD-MTX清除后重新开始。诱导治疗完成后，持续每日单药给予伊曲替尼，直至疾病进展、不可耐受的毒性或死亡。我们还探索了治疗前和治疗期间脑脊液（CSF）中循环肿瘤DNA（ctDNA）的下一代测序。伊曲替尼、HD-MTX和利妥昔单抗的组合是耐受的，具有可接受的安全性特征（无5级事件，3起4级事件）。未观察到剂量限制性毒性。15例患者中有11例在完成4个周期的伊鲁替尼/ HD-MTX/利妥昔单抗联合治疗后继续维持伊鲁替尼。15例患者中有12例（80%）出现临床应答。持续的肿瘤缓解与CSF中ctDNA的清除相关。本试验在www.clinicaltrials.gov上注册为#NCT02315326。
Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle 5 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/ HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.