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 .).

Figure 1. Efficacy End Points

Panel A shows the probability of overall survival in the two groups. Overall survival was calculated as the time from randomization to death from any cause. The median duration of follow-up for overall survival was 11.7 months in the blinatumomab group and 11.8 months in the chemotherapy group. Panel B shows the probability of overall survival in the two groups (also calculated as the time from randomization to death from any cause) when data were censored at the time of allogeneic stem-cell transplantation. The median duration of follow-up for this analysis of overall survival was 7.0 months in the blinatumomab group and 6.0 months in the chemotherapy group. Panel C shows the probability of event-free survival, which was calculated as the time from randomization until relapse after complete remission with full, partial, or incomplete hematologic recovery, or death; patients who did not achieve a complete re-mission with full, partial, or incomplete hematologic recovery were assigned an event-free duration of 1 day. The median duration of follow-up for event-free survival was 7.8 months in the blinatumomab group and 10.2 months in the chemotherapy group. All three analyses were performed in the intention-to-treat population. P values were determined by means of stratified log-rank tests.

Figure 2. Subgroup Analyses

Panel A shows the results of an analysis of overall survival in prespecified subgroups of the intention-to-treat population that were defined according to baseline characteristics. Overall survival was calculated as the time from randomization to death from any cause. Panel B shows the results of an analysis of remission rates in prespecified subgroups of the intention-to-treat population that were defined according to baseline characteristics. The remission rate was defined as the percentage of patients who had complete hematologic remission with full, partial, or incomplete hematologic recovery by week 12. For both analyses, bone marrow blast data were from the central laboratory, if available; otherwise, data from the local laboratory were used. Central and local baseline results for bone marrow blasts were missing for one patient in the blinatumomab group.