Lampson Benjamin L, Kasar Siddha N, Matos Tiago R, Morgan Elizabeth A, Rassenti Laura, Davids Matthew S, Fisher David C, Freedman Arnold S, Jacobson Caron A, Armand Philippe, Abramson Jeremy S, Arnason Jon E, Kipps Thomas J, Fein Joshua, Fernandes Stacey, Hanna John, Ritz Jerome, Kim Haesook T, Brown Jennifer R
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
Department of Pathology, Brigham and Women's Hospital, Boston, MA;
Blood. 2016 Jul 14;128(2):195-203. doi: 10.1182/blood-2016-03-707133. Epub 2016 May 31.
Idelalisib is a small-molecule inhibitor of PI3Kδ with demonstrated efficacy for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as front-line therapy, we enrolled 24 subjects in a phase 2 study consisting of 2 months of idelalisib monotherapy followed by 6 months of combination therapy with idelalisib and the anti-CD20 antibody ofatumumab. After a median follow-up period of 14.7 months, hepatotoxicity was found to be a frequent and often severe adverse event. A total of 19 subjects (79%) experienced either grade ≥1 ALT or AST elevation during the study, and 13 subjects (54%) experienced grade ≥3 transaminitis. The median time to development of transaminitis was 28 days, occurring before ofatumumab introduction. Younger age and mutated immunoglobulin heavy chain status were significant risk factors for the development of hepatotoxicity. Multiple lines of evidence suggest that this hepatotoxicity was immune mediated. A lymphocytic infiltrate was seen on liver biopsy specimens taken from 2 subjects with transaminitis, and levels of the proinflammatory cytokines CCL-3 and CCL-4 were higher in subjects experiencing hepatotoxicity. All cases of transaminitis resolved either by holding the drug, initiating immunosuppressants, or both, and rates of recurrent toxicity were lower in patients taking steroids when idelalisib was reinitiated. A decrease in peripheral blood regulatory T cells was seen in patients experiencing toxicity on therapy, which is consistent with an immune-mediated mechanism. These results suggest that caution should be taken as drugs within this class are developed for CLL, particularly in younger patients who have not received prior disease-specific therapy. This study was registered at www.clinicaltrials.gov as #NCT02135133.
idelalisib是一种PI3Kδ小分子抑制剂，已证明对复发/难治性慢性淋巴细胞白血病（CLL）的治疗有效。为了评估idelalisib作为一线治疗的效果，我们在一项2期研究中招募了24名受试者，该研究包括2个月的idelalisib单药治疗，随后是6个月的idelalisib与抗CD20抗体奥法木单抗的联合治疗。在中位随访期14.7个月后，发现肝毒性是一种常见且往往严重的不良事件。共有19名受试者（79%）在研究期间出现≥1级谷丙转氨酶（ALT）或谷草转氨酶（AST）升高，13名受试者（54%）出现≥3级转氨酶升高。转氨酶升高的中位发生时间为28天，发生在引入奥法木单抗之前。年轻和免疫球蛋白重链突变状态是肝毒性发生的重要危险因素。多条证据表明这种肝毒性是免疫介导的。在2名转氨酶升高的受试者的肝活检标本中可见淋巴细胞浸润，肝毒性受试者中促炎细胞因子CCL-3和CCL-4的水平较高。所有转氨酶升高的病例通过停药、开始使用免疫抑制剂或两者兼用均得到缓解，当重新开始使用idelalisib时，服用类固醇的患者毒性复发率较低。在治疗中出现毒性的患者外周血调节性T细胞减少，这与免疫介导机制一致。这些结果表明，在开发此类用于CLL的药物时应谨慎，特别是在未接受过先前疾病特异性治疗的年轻患者中。本研究已在www.clinicaltrials.gov上注册，注册号为#NCT02135133。
