Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia

Abstract

Adult patients with relapsed/refractory (R/R) B-precursor acute lymphoblastic leukemia (ALL) have a poor prognosis. Blinatumomab is a bispecific T-cell engager (BiTE) immuno-oncology therapy with dual specificity for CD19 and CD3 that redirects patients' CD3-positive cytotoxic T cells to lyse malignant and normal B cells. We conducted an open-label, phase 1b/2 study to determine the safety, pharmacokinetics, efficacy and recommended dose of blinatumomab in Japanese adults with R/R B-precursor ALL. Patients received 9 μg/day blinatumomab during week 1 and 28 μg/ day during weeks 2-4, with a 2-week treatment-free interval (6-week cycle); patients received 28 μg/day blinatumomab in subsequent cycles. Primary endpoints were the incidence of dose-limiting toxicities (DLT) in phase 1b and complete remission (CR)/ CR with partial hematologic recovery (CRh) within the first two cycles in phase 2. A total of 26 patients enrolled and 25 (96%) reported grade ≥3 adverse events (mostly cytopenias). There were no DLT. CR/CRh within two cycles was achieved by 4 of 5 patients (80%) in phase 1b and 8 of 21 patients (38%) in phase 2. Among patients with evaluable minimal residual disease, 4 (100%) in phase 1b and 3 (38%) in phase 2 had a complete MRD response. Median RFS for 8 patients who achieved CR/CRh in phase 2 was 5 (95% CI: 3.5-6.4) months; median OS was not estimable. There were no significant associations between maximum cytokine levels or percentage of specific cell types during cycle 1 and response. Consistent with global studies, blinatumomab appeared to be safe and efficacious in Japanese adults with R/R ALL. K E Y W O R D S acute lymphoblastic leukemia, blinatumomab, clinical study, Japan, phase 1b, refractory, relapsed | 1315 KIYOI et al.

Efficacy and safety of blinatumomab: Post hoc pooled analysis in Asian adults with relapsed/refractory B‐cell precursor acute lymphoblastic leukemia

“…Overall, the efficacy results were comparable to the global TOWER study and Study 265 conducted in Japanese patients (Table 4). 16,17 There were no obvious differences in hematologic response between the current analysis and the blinatumomab arm of TOWER and Study 265. In addition, the median duration of OS in the current analysis (11.9 months) was slightly greater than that observed in the blinatumomab arm of TOWER (7.7 months).…”

“…Currently, limited data are available on the efficacy and safety of blinatumomab in Asian patients, whose immunologic and genetic background may differ from Caucasian patients. A recent phase 1b/2 study (Study 265, NCT02412306) evaluated the safety and efficacy of blinatumomab in Japanese adults with Ph− R/R B‐cell precursor ALL 17 . No published study to date has evaluated the safety and efficacy of blinatumomab in the broader Asian population.…”

Blinatumomab in Pediatric Acute Lymphoblastic Leukemia—From Salvage to First Line Therapy (A Systematic Review)

“…In addition to the phase I/II studies in R/R ALL and both recently published phase III randomized controlled trials (RCTs) mentioned above, there are further trials ongoing for patients with a refractory or relapsed leukemia. One study in Japan is still recruiting, with adult data already published [46], but pediatric results still pending (NCT02412306). An observational retrospective study sponsored by Amgen for children and adults with Ph-chromosome-negative R/R ALL was completed, but there are no published results yet (NCT02783651).…”

Correction

“…In an article 1 titled “Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia” by Hitoshi Kiyoi, Joan D. Morris, Iekuni Oh, Yoshinobu Maeda, Hironobu Minami, Toshihiro Miyamoto, Toru Sakura, Hiroatsu Iida, Catherine A. Tuglus, Yuqi Chen, Cedric Dos Santos, James Kalabus, Abraham Anderson, Tomoko Hata, Yasuhiro Nakashima, Yukio Kobayashi, the following changes are to be made Funding Information has been changed to: Amgen and Amgen Astellas BioPharma KK. Greek symbols α and γ were included after “TNF” and “IFN” in text, respectively. In Section 2.3, “≤0 mg” was changed to “≤10 mg”. The spelling error of "single" was corrected in Section 4, in the sentence, "Adverse events were consistent with those reported with single‐agent blinatumomab in previous adult blinatumomab studies, with grade ≥3 cytopenias occurring in a substantial proportion of patients across studies. " The color code was changed in Figure 3, and units were changed from mm 2 to mm 3 .…”