Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia

Abstract

BACKGROUND Blinatumomab, a bispecific monoclonal antibody construct that enables CD3-positive T cells to recognize and eliminate CD19-positive acute lymphoblastic leukemia (ALL) blasts, was approved for use in patients with relapsed or refractory B-cell precursor ALL on the basis of single-group trials that showed efficacy and manageable toxic effects. METHODS In this multi-institutional phase 3 trial, we randomly assigned adults with heavily pretreated B-cell precursor ALL, in a 2:1 ratio, to receive either blinatumomab or standard-of-care chemotherapy. The primary end point was overall survival. RESULTS Of the 405 patients who were randomly assigned to receive blinatumomab (271 patients) or chemotherapy (134 patients), 376 patients received at least one dose. Overall survival was significantly longer in the blinatumomab group than in the chemotherapy group. The median overall survival was 7.7 months in the blinatumomab group and 4.0 months in the chemotherapy group (hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval [CI], 0.55 to 0.93; P = 0.01). Remission rates within 12 weeks after treatment initiation were significantly higher in the blinatumomab group than in the chemotherapy group, both with respect to complete remission with full hematologic recovery (34% vs. 16%, P<0.001) and with respect to complete remission with full, partial, or incomplete hematologic recovery (44% vs. 25%, P<0.001). Treatment with blinatumomab resulted in a higher rate of event-free survival than that with chemotherapy (6-month estimates, 31% vs. 12%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery, or death, 0.55; 95% CI, 0.43 to 0.71; P<0.001), as well as a longer median duration of remission (7.3 vs. 4.6 months). A total of 24% of the patients in each treatment group underwent allogeneic stem-cell transplantation. Adverse events of grade 3 or higher were reported in 87% of the patients in the blinatumomab group and in 92% of the patients in the chemotherapy group. CONCLUSIONS Treatment with blinatumomab resulted in significantly longer overall survival than chemotherapy among adult patients with relapsed or refractory B-cell precursor ALL. (Funded by Amgen; TOWER ClinicalTrials.gov number, NCT02013167.)

Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents

“…Baseline T cell and B cell concentrations in the blood were assigned at 500 and 300 cells per µL, respectively, based on the most recently reported data in relapsed/refractory acute lymphoblastic leukemia (ALL) patients who received blinatumomab treatment; 34 baseline T cell and B cell concentrations in bone marrow were assigned at 2,000 and 20,000 cells per µL, respectively, based on multiple reported assessments of bone marrow lymphocyte subsets, which include patients with advanced ALL who received blinatumomab treatment. 35–37 Other blinatumomab binding-associated parameters (e.g., KD CD3, KD receptor_CD19 ) and compound and reaction system-associated parameters (e.g., EC 50 , γ, τ reference , k τ1, k τ2 ) were assumed to be the same for in vitro and in vivo conditions. Since immune suppression is expected in patients with ALL, which may be associated with both upregulation of regulatory T cells and altered levels of cytokines, 38–40 k max for T cells from patients with relapsed or refractory ALL was assumed to be 1/3 of that from healthy T cells clone (0.0693 1/hr).…”

Immunotherapy in adult acute lymphoblastic leukemia: the role of monoclonal antibodies

“…A total of 405 patients with relapsed/refractory Ph -ALL were randomly assigned to either blinatumomab (n 5 271) or standard-ofcare chemotherapy (n 5 134). 19 The overall response rates were 45% and 30% (P 5 .007), respectively. Molecular remission rates among responders, defined as , 10 24 blasts in the first 12 weeks, were 75% and 48%, respectively.…”

Updates in Adult Acute Lymphoblastic Leukemia—Current Status of Antigen-targeted Treatments and Immunotherapy

“…EFS and remission duration were also longer with blinatumomab, while there were lower incidences of myelosuppression, and neurologic events and cytokine release syndrome potentially observed with blinatumomab were generally mild to moderate. 50 Long-term survival after blinatumomab treatment has been shown to be associated with an MRD response and potentially with a higher degree of T cell expansion. 51 Alternative therapies could be proposed to patients who remain positive for BCR-ABL transcripts more than 2 months after starting imatinib therapy after transplant.…”

“…With blinatumomab administration, CRS has been prevented with corticosteroid premedication, disease cytoreduction, and dose adjustments. 50 After CAR T cell administration, CRS has been reported from 27% to 43% of cases (Table 5). 13,64,65,69 CRS occurs within 1 to 14 days of anti-CD19 CAR T cell infusion.…”