■成人复发性或难治性B细胞急性淋巴细胞白血病或淋巴瘤(B-ALL)的选择有限,需要新的方法。伊托珠单抗奥佐大霉素(InO)已与低强度化疗联合,与历史控制相比略有改进,和剂量调整的依托泊苷,泼尼松,长春新碱,环磷酰胺,对于新诊断的ALL,阿霉素(DA-EPOCH)治疗是安全有效的。
■评估DA-EPOCH和InO在复发性或难治性B-ALL成人中的安全性和临床活性。
■这个单中心,单臂,非随机化,1期剂量递增试验纳入了复发或难治性CD22+B-ALL的成人患者,试验于2019年9月至2022年11月期间进行.招募需要至少5%的血液或骨髓母细胞或可测量的髓外疾病(EMD)。
■在第1至5天给予DA-EPOCH,而在28天周期的第8天和第15天给予InO。使用贝叶斯最佳间隔设计研究了三个剂量水平。
■主要结果是InO与DA-EPOCH合用时的最大耐受剂量,定义为产生剂量限制毒性率低于33%的最高剂量水平。次要目标包括回应率,生存估计,以及毒性作用的描述。
■总共对24名参与者进行了筛查和登记(平均年龄,46[范围,28-76]岁;男性15[62%])。先前治疗的行数中位数为3(范围,1-12).11名参与者中有3名(27%)在最高剂量水平(InO,0.6mg/m2,在第8天和第15天)经历了剂量限制性毒性,使其成为最大耐受剂量。研究期间没有死亡,研究后同种异体移植后,只有1例患者(4%;95%CI,0.1%-21%)出现了窦阻塞综合征。形态学完全缓解率为84%(95%CI,60%-97%),其中88%(95%CI,62%-98%)为流式细胞术检测阴性的残留病。6名EMD参与者中有5名经历了治疗反应。总有效率为83%(95%CI,63%-95%)。总生存率中位数,响应的持续时间,无事件生存率为17.0(95%CI,8.4-未达到),15.0(95%CI,6.7-未达到),和9.6个月(95%CI,4.5-未达到),分别。
■在这项研究中,在复发性或难治性B-ALL的成人中添加InO到DA-EPOCH是可行的,高反应率和窦状阻塞性综合征很少发生在严重预处理的人群中。许多患者能够进行研究后巩固性异基因造血细胞移植和/或嵌合抗原受体T细胞治疗。有必要对这种组合进行进一步调查。
■ClinicalTrials.gov标识符:NCT03991884。
UNASSIGNED: Options for adults with relapsed or refractory B-cell acute lymphoblastic leukemia or lymphoma (B-ALL) are limited, and new approaches are needed. Inotuzumab ozogamicin (InO) has been combined with low-intensity chemotherapy, with modest improvements over historical controls, and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH) treatment is safe and active for newly diagnosed ALL.
UNASSIGNED: To assess the safety and clinical activity of DA-EPOCH and InO in adults with relapsed or refractory B-ALL.
UNASSIGNED: This single-center, single-arm, nonrandomized, phase 1 dose-escalation
trial included adults with relapsed or refractory CD22+ B-ALL and was conducted between September 2019 and November 2022. At least 5% blood or marrow blasts or measurable extramedullary disease (EMD) was required for enrollment.
UNASSIGNED: DA-EPOCH was given on days 1 to 5, while InO was given on day 8 and day 15 of a 28-day cycle. Three dose levels were studied using a bayesian optimal interval design.
UNASSIGNED: The primary outcome was the maximum tolerated dose of InO when combined with DA-EPOCH, defined as the highest dose level that produced a rate of dose-limiting toxicity below 33%. Secondary objectives included response rates, survival estimates, and descriptions of toxic effects.
UNASSIGNED: A total of 24 participants were screened and enrolled (median age, 46 [range, 28-76] years; 15 [62%] male). The median number of lines of prior therapy was 3 (range, 1-12). Three of 11 participants (27%) treated at the highest dose level (InO, 0.6 mg/m2, on day 8 and day 15) experienced dose-limiting toxicity, making this the maximum tolerated dose. No deaths occurred during the
study, and only 1 patient (4%; 95% CI, 0.1%-21%) developed sinusoidal obstructive syndrome after poststudy allograft. The morphologic complete response rate was 84% (95% CI, 60%-97%), 88% (95% CI, 62%-98%) of which was measurable residual disease negative by flow cytometry. Five of 6 participants with EMD experienced treatment response. The overall response rate was 83% (95% CI, 63%-95%). Median overall survival, duration of response, and event-free survival were 17.0 (95% CI, 8.4-not reached), 15.0 (95% CI, 6.7-not reached), and 9.6 (95% CI, 4.5-not reached) months, respectively.
UNASSIGNED: In this
study, adding InO to DA-EPOCH in adults with relapsed or refractory B-ALL was feasible, with high response rates and sinusoidal obstructive syndrome occurring rarely in a heavily pretreated population. Many patients were able to proceed to poststudy consolidative allogeneic hematopoietic cell transplant and/or chimeric antigen receptor T-cell therapy. Further investigation of this combination is warranted.
UNASSIGNED: ClinicalTrials.gov Identifier: NCT03991884.