Bispecific CD19-Directed CD3 T-Cell Engager Blinatumomab Active in Adults With Relapsed/Refractory B-Cell Precursor ALL
In a phase II study reported in The Lancet Oncology, Topp et al found that the bispecific CD19-directed CD3 T-cell engager (BiTE) blinatumomab (Blincyto) was highly active in adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). Blinatumomab binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells. The study supported the recent FDA accelerated approval of blinatumomab in treating Philadelphia chromosome–negative relapsed/refractory B-cell precursor ALL.
Study Details
In the open-label trial, 189 adults with Philadelphia chromosome–negative primary refractory or relapsed ALL were enrolled between January 2012 and October 2013 and received blinatumomab at 9 μg/d for the first 7 days and 28 μg/d thereafter by continuous intravenous infusion over 4 weeks every 6 weeks for up to five cycles. Relapsed ALL was defined as first relapse within 12 months of first remission, relapse within 12 months after allogeneic hematopoietic stem-cell transplantation, or no response to or relapse after first salvage therapy or beyond. The primary endpoint was complete remission or complete remission with partial hematologic recovery of peripheral blood counts within the first two cycles in the intention-to-treat population.
Patients had a median age of 39 years, 63% were men, 50% were from Europe and 50% from the United States, 635 had one or two previous lines of salvage therapy, 34% had previous allogeneic stem cell transplantation, and 60% had marrow blast count ≥ 50%.
Responses
After two cycles of treatment, 81 patients (43%, 95% confidence interval = 36%–50%) had complete remission (33%) or complete remission with partial hematologic recovery (10%). Complete remission or complete remission with partial hematologic recovery occurred in 73% of patients with < 50% of bone marrow blasts and 29% of those with ≥ 50% blasts.
Median relapse-free survival was 5.9 months in patients with complete remission or complete remission with partial hematologic recovery, 6.9 months in those with complete remission, and 5.0 months in those with complete remission with partial hematologic recovery. Median overall survival was 6.1 months among all patients and was significantly prolonged in those with remission (relative odds ratio = 0.13, P < .0001). Complete remission or complete remission with partial hematologic recovery occurred in similar proportions of patients with (45%) or without (42%) previous allogeneic hematopoietic stem cell transplantation.
Of patients with complete remission or complete remission with partial hematologic recovery during the first two cycles, 40% subsequently received allogeneic hematopoietic stem cell transplantation. Among 73 patients who achieved complete remission or complete remission with partial hematologic recovery and were evaluable for minimal residual disease, 60 (82%) patients achieved minimal residual disease response. Median relapse-free survival for minimal residual disease responders was 6.9 vs 2.3 months for nonresponders, and median overall survival was 11.5 vs 6.7 months.
Adverse Events
Grade 3, 4, and 5 adverse events occurred in 38%, 30%, and 15% of patients. The most common grade ≥ 3 adverse events were febrile neutropenia (25%), neutropenia (16%), and anemia (14%). Three (2%) patients had grade 3 cytokine release syndrome.
Neurologic adverse events of any grade occurred in 52% of patients, including grade ≥ 3 events in 13%. Neurologic events led to treatment interruption in 29 patients (15%); 10 achieved complete remission or complete remission with partial hematologic recovery before treatment was halted, and 8 of the remaining 19 patients achieved complete remission or complete remission with partial hematologic recovery after treatment was resumed.
Fatal adverse events consisted mainly of death from infection. Three deaths, due to sepsis, Escherichia coli sepsis, and Candida infection, were considered treatment-related.
The investigators concluded: “Single-agent blinatumomab showed antileukaemia activity in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia characterised by negative prognostic factors. Further assessment of blinatumomab treatment earlier in the course of the disease and in combination with other treatment approaches is warranted.”
Max S. Topp, MD, of Universitätsklinikum Würzburg, is the corresponding author for The Lancet Oncology article.
The study was funded by Amgen. For full disclosures of the study authors, visit www.thelancet.com.
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