Phase 2 Study of Blinatumomab in Japanese Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia (R/R ALL)
Authors: Kobayashi Yukio , Zimmerman Zachary F. , Oh Iekuni , Maeda Yoshinobu , Minami Hironobu , Miyamoto Toshihiro , Sakura Toru , Iida Hiroatsu , Chen Yuqi , Kiyoi Hitoshi 
Published: October 2019

Abstract
Introduction: Blinatumomab is an anti-CD3/CD19 bispecific T-cell engager antibody construct that has antileukemic activity in adult patients with R/R ALL. The objectives of this open-label, multicenter, phase 2 study were to determine the efficacy and safety of the recommended dose level of blinatumomab (identified in the phase 1b part of the study) in Japanese adults with R/R B-precursor ALL.
Methods: Eligible patients were ≥ 18 years old with R/R ALL (first remission duration ≤ 12 months, after first salvage, or within 12 months after allogeneic hematopoietic stem cell transplantation [alloHSCT]), > 5% blasts, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, and no central nervous system pathology. The primary endpoint was complete remission/complete remission with partial hematological recovery (CR/CRh) within 2 cycles of treatment with blinatumomab; additional endpoints included relapse-free survival (RFS), overall survival (OS), minimal residual disease (MRD) response, the incidence and severity of adverse events (AEs), and the incidence of anti-blinatumomab antibody formation. Consistent with global studies, the selected phase 2 dose identified in the phase 1b part was 9-28 μg/day, and patients received induction blinatumomab for 4 weeks by continuous intravenous infusion (cycle 1/week 1: 9 μg/day; cycle 1/weeks 2-4: 28 μg/day; subsequent cycles: 28 μg/day) followed by 2 weeks of no blinatumomab (each cycle). Patients who achieved a bone marrow response (≤ 5% blasts) within 2 induction cycles received additional consolidation cycles of blinatumomab, up to a maximum of 5 total induction/consolidation cycles.
Results: Twenty-one patients enrolled between April 2016 and June 2017 received blinatumomab 9-28 μg/day (median 2 [range, 1-3] cycles). Twelve of the 21 patients (57%) were women; the median (range) age was 43 (18-55) years; 9 patients (43%) had prior HSCT; 7 patients (33%) had 1 prior salvage therapy, 4 patients had 2 prior salvage therapies, and 3 patients had more than 2 prior salvage therapies; and the median (range) percentage of bone marrow blasts was 69% (7%-96%). Responses during the first 2 cycles of treatment with blinatumomab are shown in the table. CR/CRh during the first 2 cycles was observed in 8 patients (38%); 3 of 7 patients who achieved CR/CRh and had evaluable MRD had a complete MRD response. Among the 8 patients who achieved CR/CRh during the first 2 cycles, the median RFS was 5 months (95% CI: 3.5-6.4 months), with a median (range) follow-up time of 2.2 (0-2.8) months; the Kaplan-Meier estimate of RFS was 100%, 50%, and 0% at 3, 6, and 12 months, respectively. At the data cutoff date (August 24, 2017), 2 patients had died, and OS was not estimable. Fourteen patients (67%) received an HSCT during long-term follow-up, 10 (48%) of whom did not receive other anti-cancer therapy before HSCT; 5 of the 10 patients achieved CR/CRh during the blinatumomab treatment period. All 21 patients reported AEs: 21 (100%) with grade ≥ 3 AEs, 14 (67%) with grade ≥ 4 AEs, 7 (33%) with serious AEs, 4 (19%) with AEs that led to interruption/discontinuation of blinatumomab, and 1 (5%) with a fatal AE (tumor lysis syndrome in the setting of disease progression). The most common AEs (≥ 10 patients) were pyrexia in 15 patients (71%) and febrile neutropenia (all grade ≥ 3) in 10 patients (48%). Eight patients (38%) had cytokine release syndrome (1 serious, grade ≥ 3), and 9 patients (43%) had neurologic events (1 grade ≥ 3). Other serious AEs were decreased neutrophil count (2 patients) and bacteremia, colitis, decreased appetite, and device-related infection (1 patient each). No anti-blinatumomab antibodies were detected in any patient.
Conclusions: This study demonstrated the efficacy and safety of the recommended dose level of blinatumomab in a high-risk adult R/R ALL population. Response rates in Japanese patients were consistent with those in global studies, and no new safety signals were identified.

Disclosures
Kobayashi: Ohtuka: Research Funding; Pfizer: Research Funding; Astellas: Research Funding. Zimmerman:Amgen Inc.: Employment, Equity Ownership. Minami:Kyowa-Kirin: Honoraria, Research Funding; MSD: Honoraria, Other: Clinical Trial, Research Funding; Ono Yakuhin: Honoraria, Other: Clinical Trial, Research Funding; Behringer: Honoraria, Research Funding; AstraZeneca: Other: Clinical Trial; Pfizer: Honoraria, Research Funding; Teijin Pharma: Research Funding; Astellas: Research Funding; Ohtsuka: Honoraria; Taiho: Honoraria, Other: Clinical Trial, Research Funding; Bristol-Myers Squibb: Honoraria, Other: Clinical Trial, Research Funding; Kowa: Honoraria; Eizai: Honoraria, Research Funding; Taisho-Toyama: Research Funding; DaiNihonSumitomo: Honoraria, Research Funding; DaiichiSankyo: Honoraria, Other: Clinical Trial, Research Funding; Chugai: Honoraria, Other: Clinical Trial, Research Funding; Janssen: Honoraria; Celgene: Clinical Trial, Honoraria; Takeda: Honoraria, Research Funding; Shire Japan: Honoraria; Eizai: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Bayer: Honoraria, Other: Clinical Trial, Research Funding; Merck Serono: Honoraria; Nihon Shinyaku: Research Funding; Lilly: Honoraria, Research Funding; Yakult: Research Funding; Nippon Chemiphar: Honoraria, Research Funding; Mochida: Honoraria; Asahi-Kasei Pharma: Research Funding. Iida:Chugai Pharmaceutical Co., Ltd.: Research Funding. Chen:Amgen, Inc: Employment, Equity Ownership. Kiyoi:Kyowa Hakko Kirin Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Celgene Corporation: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; FUJIFILM Corporation: Research Funding; Phizer Japan Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Bristol-Myers Squibb: Honoraria; Zenyaku Kogyo Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Sanofi K.K.: Research Funding.