Barr Paul M, Brown Jennifer R, Hillmen Peter, O'Brien Susan, Barrientos Jacqueline C, Reddy Nishitha M, Coutre Steven, Mulligan Stephen P, Jaeger Ulrich, Furman Richard R, Cymbalista Florence, Montillo Marco, Dearden Claire, Robak Tadeusz, Moreno Carol, Pagel John M, Burger Jan A, Suzuki Samuel, Sukbuntherng Juthamas, Cole George, James Danelle F, Byrd John C
Wilmot Cancer Institute, University of Rochester, Rochester, NY.
Dana-Farber Cancer Institute, Boston, MA.
Blood. 2017 May 11;129(19):2612-2615. doi: 10.1182/blood-2016-12-737346. Epub 2017 Apr 3.
Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase (BTK), at a once-daily dose of 420 mg achieved BTK active-site occupancy in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) that was maintained at 24 hours. It is unknown if intermittent interruption of ibrutinib therapy contributes to altered clinical outcomes. We therefore evaluated the effect of ibrutinib dose adherence on patient outcomes in the phase 3 RESONATE trial. The overall mean dose intensity (DI) was 95% with median treatment duration of ∼9 months. Pharmacokinetic assessment of ibrutinib exposure at 420-mg dose suggested similar exposure regardless of patient weight or age. As assessed by independent review committee, patients with higher DI experienced longer median progression-free survival (PFS) compared with those with lower DI regardless of del17p and/or status. Of 79 patients requiring a drug hold, treatment was restarted at the original dose in 73 (92%) patients. Mean duration of a missed-dose event was 18.7 days (range, 8-56). Patients missing ≥8 consecutive days of ibrutinib had a shorter median PFS vs those missing <8 days (10.9 months vs not reached). These results support sustained adherence to once-daily ibrutinib dosing at 420 mg as clinically feasible to achieve optimal outcomes in patients with previously treated CLL. The trial was registered at www.clinicaltrials.gov as #NCT01578707.
依鲁替尼是一种布鲁顿酪氨酸激酶（BTK）口服抑制剂，每日一次剂量为420mg时，可使慢性淋巴细胞白血病（CLL）/小淋巴细胞淋巴瘤（SLL）患者的BTK活性位点占有率在24小时内保持稳定。依鲁替尼治疗的间歇性中断是否会导致临床结果改变尚不清楚。因此，我们在3期RESONATE试验中评估了依鲁替尼剂量依从性对患者预后的影响。总体平均剂量强度（DI）为95%，中位治疗持续时间约为9个月。对420mg剂量依鲁替尼暴露的药代动力学评估表明，无论患者体重或年龄如何，暴露情况相似。经独立审查委员会评估，与DI较低的患者相比，DI较高的患者中位无进展生存期（PFS）更长，无论其是否存在del17p和/或状态如何。在79例需要停药的患者中，73例（92%）患者以原剂量重新开始治疗。漏服一剂事件的平均持续时间为18.7天（范围为8 - 56天）。与漏服依鲁替尼少于8天的患者相比，连续漏服≥8天依鲁替尼的患者中位PFS更短（10.9个月对未达到）。这些结果支持在临床上可行的情况下持续依从每日一次420mg依鲁替尼给药，以在先前治疗的CLL患者中实现最佳预后。该试验已在www.clinicaltrials.gov上注册，编号为#NCT01578707。
