ImportanceOptions 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.ObjectiveTo assess the safety and clinical activity of DA-EPOCH and InO in adults with relapsed or refractory B-ALL.Design, Setting, and ParticipantsThis 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.InterventionsDA-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.Main Outcomes and MeasuresThe 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.ResultsA 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.ConclusionsIn 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.Trial RegistrationClinicalTrials.gov Identifier: NCT03991884

中文翻译：

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剂量调整后的 EPOCH 加 Inotuzumab Ozogamicin 用于治疗成人复发性或难治性 B 细胞 ALL


重要性 对于患有复发性或难治性 B 细胞急性淋巴细胞白血病或淋巴瘤 (B-ALL) 的成人患者来说，治疗选择有限，需要新的方法。 Inotuzumab ozogamicin (InO) 与低强度化疗相结合，与历史对照相比略有改善，剂量调整的依托泊苷、泼尼松、长春新碱、环磷酰胺和阿霉素 (DA-EPOCH) 治疗对于新诊断的 ALL 是安全且有效的。目的评估 DA-EPOCH 和 InO 在成人复发或难治性 B-ALL 患者中的安全性和临床活性。设计、设置和参与者这项单中心、单臂、非随机、1 期剂量递增试验包括患有复发或难治性 B-ALL 的成人。难治性 CD22+ B-ALL，于 2019 年 9 月至 2022 年 11 月期间进行。入组需要至少 5% 的血液或骨髓母细胞或可测量的髓外疾病 (EMD)。干预措施 DA-EPOCH 在第 1 至 5 天给予，同时给予 InO在 28 天周期的第 8 天和第 15 天。使用贝叶斯最佳间隔设计研究了三个剂量水平。 主要结果和措施主要结果是 InO 与 DA-EPOCH 联合使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。次要目标包括缓解率、生存估计和毒性作用描述。结果 总共筛选并登记了 24 名参与者（中位年龄，46 [范围，28-76] 岁；15 名 [62%] 男性）。先前治疗的中位线数为 3（范围：1-12）。在最高剂量水平（InO，0.6 mg/m2，第 8 天和第 15 天）治疗的 11 名参与者中，有 3 名 (27%) 经历了剂量限制性毒性，使其成为最大耐受剂量。研究期间没有发生死亡，只有 1 名患者死亡（4%；95% CI，0.1%-21%)在研究后同种异体移植后出现窦窦阻塞综合征。形态学完全缓解率为 84% (95% CI, 60%-97%)、88% (95% CI, 62%-98%)，其中通过流式细胞术可测量到的残留病灶呈阴性。 6 名患有 EMD 的参与者中有 5 名出现了治疗反应。总体缓解率为 83%（95% CI，63%-95%）。中位总生存期、缓解持续时间和无事件生存期分别为 17.0（95% CI，8.4-未达到）、15.0（95% CI，6.7-未达到）和 9.6（95% CI，4.5-未达到）结论在这项研究中，在患有复发性或难治性 B-ALL 的成人患者中，在 DA-EPOCH 中添加 InO 是可行的，具有高缓解率，并且在经过大量治疗的人群中很少发生窦窦阻塞综合征。许多患者能够继续进行研究后巩固性同种异体造血细胞移植和/或嵌合抗原受体 T 细胞治疗。有必要对该组合进行进一步研究。试验注册临床试验。政府标识符：NCT03991884