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The FDA has granted an accelerated approval to blinatumomab (Blincyto) for the treatment of pediatric and adolescent patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia.
Lia Gore, MD
The FDA has granted an accelerated approval to blinatumomab (Blincyto) for the treatment of pediatric and adolescent patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
The approval of the anti-CD19 immunotherapy in this setting was based on data from a single-arm phase I/II trial, known as Study 205, which met its primary phase II endpoint of complete remission (CR) within the first 2 cycles of blinatumomab. All patient treatment in the trial has been completed, and individuals are now being assessed for long-term efficacy, according to Amgen, the developer of the drug.
“Blincyto represents the first new treatment option for childhood acute lymphoblastic leukemia approved in more than 10 years,” Lia Gore, MD, professor of Pediatrics, Medical Oncology and Hematology, University of Colorado Anschutz Medical Campus, and one of the lead investigators on Study 205, said in a statement. “The opportunity to enhance the treatment landscape of this disease for children with this drug is very exciting.”
The most common grade ≥3 adverse events (AEs) among patients receiving the recommended dose (n = 70) were anemia, thrombocytopenia, febrile neutropenia, hypokalemia, and neutropenia. Serious AEs were comparable to those previously reported for blinatumomab in adult patients.
In previously published data from phase I of Study 205, the CR rate was approximately 32% among 41 patients with relapsed/refractory ALL.1 Among the patients who achieved a CR, 77% were minimum residual disease (MRD)—negative, the median relapse free survival (RFS) was 8.3 months, and the median overall survival (OS) was 5.7 months. Preliminary results for 39 patients from the phase II part of the study showed that the CR rate was 31% (n = 12).2 Among patients reaching a CR, 42% were MRD-negative, the median RFS was 5.6 months, and the median OS was 4.3 months.
As an accelerated approval, the continued approval of blinatumomab in this setting is contingent upon results from a confirmatory trial.
Following a breakthrough therapy designation in July 2014, the FDA initially granted blinatumomab an accelerated approval for adult patients in this setting in December 2014, based on phase II data demonstrating strong clinical activity with the agent.
In the pivotal phase II study, the CR rate was 32.4% (95% CI, 25.7-39.7), the CR with partial hematological recovery (CRh) rate was 9.2% (95% CI, 5.4-14.3), and the combined CR/CRh rate was 41.6% (95% CI, 34.4-49.1). Overall, 80% of patients who achieved a CR also responded by MRD testing. Approximately 39% of patients who achieved a CR/CRh went on to receive an HSCT.
The most common all-grade AEs were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), rash (21%), tremor (20%), and constipation (20%). In all, 3 patients experienced treatment-related grade 5 AEs: sepsis (n = 2) and candida infection (n = 1).
Neurological side effects occurred in approximately 50% of patients. Additionally, 11% experienced cytokine release syndrome. To address these side effects, the FDA approved blinatumomab with a Boxed Warning and Risk Evaluation and Mitigation Strategy (REMS).
Results from the confirmatory phase III TOWER trial were presented in June at the 2016 European Hematology Association Congress. In the study, the median overall survival with blinatumomab was 7.7 months versus 4 months with standard chemotherapy in patients with Philadelphia chromosome—negative relapsed or refractory B-cell precursor ALL.
The open-label phase III TOWER trial randomized 405 patients in a 2:1 ratio to blinatumomab (n = 271) or investigator’s choice of 1 of 4 standard chemotherapy regimens (n = 134). Treatment with blinatumomab reduced the risk of death by 29% versus standard chemotherapy (HR, 0.71; 95% CI, 0.55-0.93; P = .012).
The CR rate with blinatumomab was 39% versus 19% with standard chemotherapy (P <.001). The combined CR/CRh/CRi rates were 46% versus 28%, respectively (P = .001). The adverse event (AE) profile was similar between the 2 arms and consistent with previous studies of blinatumomab.
Blinatumomab is a recombinant, single-chain monoclonal antibody that possesses antigen-recognition sites for CD3 and CD19. The CD3 complex consists of T cell surface glycoproteins, while CD19 is a tumor-associated antigen. The combination of these recognition sites into 1 therapy is thought to promote cytotoxic T lymphocyte and helper T lymphocyte activity against CD19-expressing B lymphocytes.
The multicenter, dose-finding, efficacy Study 205 trial accrued 93 patients aged <18 years with Ph- B-cell precursor ALL who were refractory, had relapsed at least twice, or relapsed after an allogeneic hematopoietic stem cell transplantation (HSCT). Following the phase I portion of the study, the recommended blinatumomab regimen proposed by an independent monitoring panel for phase II was stepwise dosing of 5/15-μg/m²/day.