Lymphoma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY.
Department of Medicine, Weill Cornell Medical College, New York, NY; and.
Blood. 2018 Apr 19;131(16):1805-1808. doi: 10.1182/blood-2017-08-802561. Epub 2018 Jan 31.
In the postrituximab era, approximately half of the patients with relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) fail to achieve a chemosensitive response to standard salvage therapy, and are thus ineligible to proceed to autologous stem cell transplantation with curative intent. The Bruton tyrosine kinase inhibitor ibrutinib demonstrates single-agent activity in rel/ref DLBCL, particularly of non-germinal center (non-GC) cell of origin. We conducted a single-center phase 1 study evaluating dose-escalated ibrutinib, in a 3-by-3 design, in combination with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in physiologically transplant-eligible rel/ref DLBCL patients. Twenty-one patients have been treated and are evaluable for toxicity with no dose-limiting toxicities observed through expansion with ibrutinib at 840 mg daily at dose level 3. Of the 20 patients evaluable for response, per modern International Conference on Malignant Lymphoma criteria, 11 patients achieved complete remission (CR) and 7 patients achieved partial remission for an overall response rate of 90%. All evaluable patients with non-GC DLBCL achieved a metabolic CR. Ibrutinib in combination with R-ICE demonstrates tolerability and efficacy in rel/ref DLBCL, particularly of non-GC phenotype. This treatment program warrants further investigation in later-phase studies. This trial was registered at www.clinicaltrials.gov as #NCT02219737.
在利妥昔单抗治疗后时代，大约一半复发或难治性（rel/ref）弥漫性大 B 细胞淋巴瘤（DLBCL）患者对标准挽救性治疗无化疗敏感性反应，因此不符合进行自体造血干细胞移植以达到治愈的条件。布鲁顿酪氨酸激酶抑制剂伊布替尼在 rel/ref DLBCL 中具有单药活性，尤其是非生发中心（non-GC）起源的细胞。我们进行了一项单中心 1 期研究，评估了在生理上适合移植的 rel/ref DLBCL 患者中，伊布替尼联合利妥昔单抗、异环磷酰胺、卡铂和依托泊苷（R-ICE）的剂量递增 3×3 设计。21 例患者已接受治疗并可评估毒性，在剂量扩展阶段，伊布替尼的每日剂量为 840mg，未观察到 3 级剂量限制毒性。在 20 例可评估反应的患者中，根据现代国际恶性淋巴瘤会议标准，11 例患者达到完全缓解（CR），7 例患者达到部分缓解，总缓解率为 90%。所有可评估的非 GC DLBCL 患者均达到代谢性 CR。伊布替尼联合 R-ICE 在 rel/ref DLBCL 中具有耐受性和疗效，尤其是在非 GC 表型中。该治疗方案值得在后期研究中进一步探索。该试验在 www.clinicaltrials.gov 上注册，编号为 #NCT02219737。
