奥英妥珠单抗治疗复发或难治性急性淋巴细胞白血病成年患者的肝脏不良事件情况：开放标签、随机、3期INO-VATE研究结果

Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study.

作者信息

Kantarjian Hagop M, DeAngelo Daniel J, Advani Anjali S, Stelljes Matthias, Kebriaei Partow, Cassaday Ryan D, Merchant Akil A, Fujishima Naohito, Uchida Toshiki, Calbacho Maria, Ejduk Anna A, O'Brien Susan M, Jabbour Elias J, Zhang Hui, Sleight Barbara J, Vandendries Erik R, Marks David I

机构信息

University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Dana-Farber Cancer Institute, Boston, MA, USA.

出版信息

Lancet Haematol. 2017 Aug;4(8):e387-e398. doi: 10.1016/S2352-3026(17)30103-5. Epub 2017 Jul 4.

DOI:10.1016/S2352-3026(17)30103-5

PMID:28687420

Abstract

BACKGROUND

The INO-VATE study demonstrated efficacy and safety of inotuzumab ozogamicin versus standard care in adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Here, we report the frequency of, and potential risk factors for, hepatotoxicity in patients in this trial and after treatment and subsequent haemopoietic stem-cell transplantation (HSCT).

METHODS

In this open-label, phase 3, multicentre, international study, adults with relapsed or refractory, CD22-positive, Philadelphia chromosome (Ph)-positive or Ph-negative B-cell acute lymphoblastic leukaemia who were due to receive first or second salvage treatment were randomly assigned (1:1) via an interactive voice response system to receive inotuzumab ozogamicin (starting dose 1·8 mg/m per cycle [0·8 mg/m on day 1; 0·5 mg/m on days 8 and 15 of a 21-28 day cycle for ≤6 cycles]) or standard care (either fludarabine plus cytarabine plus granulocyte colony-stimulating factor, mitoxantrone plus cytarabine, or high-dose cytarabine). Stratification factors at randomisation were duration of first remission (<12 months vs ≥12 months), salvage treatment phase (first vs second), and age (<55 years vs ≥55 years). We present data up to March 8, 2016. At this cutoff date, all patients had been discontinued from treatment but 54 patients were continuing in long-term follow-up. Long-term follow-up has now been completed, with the final patient's last visit on Jan 4, 2017. This prespecified safety analysis describes investigator-assessed treatment-emergent hepatotoxicity, including sinusoidal obstruction syndrome (also known as veno-occlusive disease) in patients during study treatment or thereafter (without follow-up HSCT) and after study treatment and subsequent HSCT, for all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT01564784.

FINDINGS

Between Aug 27, 2012, and and the data cutoff of March 8, 2016, 326 patients were randomly assigned to receive inotuzumab ozogamicin (n=164) or standard care (n=162). 164 patients in the inotuzumab ozogamicin group and 143 in the standard care group received at least one dose of study treatment and were included in the safety population. At data cutoff, median duration of treatment (induction) was 8·9 weeks (IQR 4·1-13·1) in the inotuzumab ozogamicin group and 0·9 weeks (0·9-1·1) in the standard care group. Treatment-emergent hepatotoxicities (of all grades) were more frequent in the inotuzumab ozogamicin group (83 [51%] of 164 patients) than in the standard care group (49 [34%] of 143 patients). The frequency of sinusoidal obstruction syndrome-comprising events occurring during treatment (or follow-up without HSCT) and after treatment and subsequent HSCT-was higher in the inotuzumab ozogamicin group (22 [13%]; 18 [82%] of which were grade 3 or worse) than in the standard care group (one [<1%]). During study therapy or follow-up without HSCT, five (3%) patients in the inotuzumab ozogamicin group developed sinusoidal obstruction syndrome compared with no patients in the standard care group. Of the 77 patients who received inotuzumab ozogamicin and proceeded to HSCT, 17 (22%) had sinusoidal obstruction syndrome; five events after follow-up HSCT were fatal. Of 32 patients who received standard care and proceeded to HSCT, one (3%) had (non-fatal) sinusoidal obstruction syndrome that was ongoing at the time of death due to septic shock. In multivariate analysis, conditioning with two alkylating agents (p=0·015 vs one alkylating agent) and last available pre-HSCT bilirubin concentration of greater than or equal to the upper limit of normal (ULN; p=0·009 vs <ULN) were associated with increased risk of sinusoidal obstruction syndrome in patients who received inotuzumab ozogamicin. The estimated hazard ratio for overall survival in patients with follow-up HSCT (inotuzumab ozogamicin vs standard care) was 1·227 (97·5% CI 0·656-2·292; one-sided stratified log-rank p=0·77); at 24 months, the estimated probability of survival was 38·9% (95% CI 27·6-50·0) in the inotuzumab ozogamicin group versus 28·7% (11·2-49·1) in the standard care group.

INTERPRETATION

Treatment with inotuzumab ozogamicin is associated with increased hepatotoxicity, especially after follow-up HSCT, compared with standard care.

FUNDING

Pfizer.

摘要

背景

INO-VATE研究证明了与标准治疗相比，吉妥珠单抗奥唑米星治疗复发或难治性B细胞急性淋巴细胞白血病成人患者的疗效和安全性。在此，我们报告该试验患者以及治疗后和后续造血干细胞移植（HSCT）期间肝毒性的发生频率及潜在风险因素。

方法

在这项开放标签、3期、多中心、国际研究中，复发或难治性、CD22阳性、费城染色体（Ph）阳性或Ph阴性B细胞急性淋巴细胞白血病且即将接受首次或第二次挽救治疗的成人患者，通过交互式语音应答系统随机分配（1:1）接受吉妥珠单抗奥唑米星（起始剂量1.8mg/m²/周期[第1天0.8mg/m²；21-28天周期的第8天和第15天各0.5mg/m²，最多6个周期]）或标准治疗（氟达拉滨加阿糖胞苷加粒细胞集落刺激因子、米托蒽醌加阿糖胞苷或大剂量阿糖胞苷）。随机分组时的分层因素为首次缓解持续时间（<12个月对≥12个月）、挽救治疗阶段（首次对第二次）和年龄（<55岁对≥55岁）。我们展示截至2016年3月8日的数据。在这个截止日期，所有患者均已停止治疗，但有54例患者仍在长期随访中。长期随访现已完成，最后一名患者的末次访视时间为2017年1月4日。这项预先设定的安全性分析描述了研究者评估的治疗中出现的肝毒性，包括研究治疗期间或之后（无后续HSCT）以及研究治疗后和后续HSCT后患者的窦性阻塞综合征（也称为静脉闭塞性疾病），纳入所有接受至少一剂研究治疗的患者。本研究已在ClinicalTrials.gov注册，编号为NCT01564784。

结果

在2012年8月27日至2016年3月8日数据截止期间，326例患者被随机分配接受吉妥珠单抗奥唑米星（n = 164）或标准治疗（n = 162）。吉妥珠单抗奥唑米星组的164例患者和标准治疗组的143例患者接受了至少一剂研究治疗，并被纳入安全性分析人群。在数据截止时，吉妥珠单抗奥唑米星组的中位治疗（诱导）持续时间为8.9周（IQR 4.1 - 13.1），标准治疗组为0.9周（0.9 - 1.1）。吉妥珠单抗奥唑米星组治疗中出现的肝毒性（所有级别）比标准治疗组更常见（164例患者中的83例[51%]对143例患者中的49例[34%]）。在治疗期间（或无HSCT的随访期间）以及治疗后和后续HSCT后发生的窦性阻塞综合征相关事件的频率，吉妥珠单抗奥唑米星组高于标准治疗组（22例[13%]；其中18例[82%]为3级或更严重）（标准治疗组1例[<1%]）。在研究治疗或无HSCT的随访期间，吉妥珠单抗奥唑米星组有5例（3%）患者发生窦性阻塞综合征，而标准治疗组无患者发生。在接受吉妥珠单抗奥唑米星并进行HSCT的77例患者中，17例（22%）发生窦性阻塞综合征；5例随访HSCT后的事件是致命的。在接受标准治疗并进行HSCT的32例患者中，1例（3%）发生（非致命）窦性阻塞综合征，在因感染性休克死亡时仍持续存在。在多变量分析中，与使用一种烷化剂相比，使用两种烷化剂进行预处理（p = 0.015）以及最后一次可用的HSCT前胆红素浓度大于或等于正常上限（ULN；p = 0.009对<ULN）与接受吉妥珠单抗奥唑米星治疗的患者发生窦性阻塞综合征的风险增加相关。接受随访HSCT患者的总生存估计风险比（吉妥珠单抗奥唑米星对比标准治疗）为1.227（97.5%CI 0.656 - 2.292；单侧分层对数秩p = 0.77）；在24个月时，吉妥珠单抗奥唑米星组的估计生存概率为38.9%（95%CI 27.6 - 50.0），标准治疗组为28.7%（11.2 - 49.1）。