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Adding Blinatumomab to Consolidation Chemotherapy Improves OS in Adult Patients in MRD-negative Remission from BCP-ALL

Findings from E1910 study
12 Aug 2024
Immunotherapy;  Cytotoxic Therapy
Leukaemias

In a randomised phase III, E1910 study, conducted through the National Clinical Trials Network of the US National Cancer Institute (NCI), the investigators from the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network (ECOG-ACRIN) showed an overall survival (OS) benefit with adding blinatumomab to consolidation chemotherapy in patients with BCR::ABL1-negative disease who were between 30 and 70 years of age and had B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) in measurable residual disease (MRD)-negative remission. Although the study was not powered for subgroup analyses, patients younger than 55 years of age appeared to have the greatest benefit.

The incidence of reported neuropsychiatric adverse events was higher with blinatumomab than with chemotherapy alone. The findings are reported by Dr. Mark R. Litzow of the Division of Hematology, Mayo Clinic in Rochester, MN, US and colleagues on 24 July 2024 in The New England Journal of Medicine.

The authors wrote in the background that outcomes in adults with BCP-ALL are inferior to those in children, owing in part to the increased frequency of high-risk genetic abnormalities and to the side effects of high-dose chemotherapy.

Blinatumomab is a bispecific T-cell engager molecule composed of an anti-CD19 variable region linked to an anti-CD3 variable region that brings T-cells in proximity to leukaemic blasts to form cytolytic synapses, leading to apoptosis and lysis of the blasts.

A phase III randomised study of blinatumomab as compared with chemotherapy for the treatment of relapsed or refractory BCR::ABL1-negative BCP-ALL (with :: indicating fusion) showed improved outcomes and led to the approval of blinatumomab by the US Food and Drug Administration (FDA) for this indication in 2014.

A subsequent study involving patients with MRD-positive BCP-ALL showed that after one 4-week cycle of blinatumomab, 78% of the patients had MRD-negative status. This finding led the FDA to expand the approval of blinatumomab to include MRD-positive BCP-ALL in 2018.

Adults with BCP-ALL who have MRD-negative remission after induction chemotherapy have a better prognosis than patients with MRD-positive status, but they still frequently have a relapse.

In E1910 study, the investigators randomly assigned patients 30 to 70 years of age with BCR::ABL1-negative BCP-ALL who had MRD-negative remission (defined as <0.01% leukaemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary endpoint was OS, and relapse-free survival (RFS) was a secondary endpoint.

The data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups.

At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to OS which was at 3 years 85% versus 68% (hazard ratio [HR] for death 0.41, 95% confidence interval [CI] 0.23 to 0.73; p = 0.002). The 3-year RFS was 80% with blinatumomab and 64% with chemotherapy alone (HR for relapse or death 0.53, 95% CI 0.32 to 0.87).

Data on treatment-related adverse events were available for 479 enrolled patients. Among the patients who had MRD-negative status and received blinatumomab, a treatment-related non-haematologic side effect of grade 3 occurred in 43%, of grade 4 in 14%, and of grade 5 in 2%, as compared with 36%, 15%, and 1%, respectively, among patients with MRD-negative status in the chemotherapy-only group (p = 0.87).

A treatment-related neurologic or psychiatric adverse event of grade 3 or higher occurred in 23% of the 111 patients who started treatment with blinatumomab, as compared with 5% of the 112 patients in the chemotherapy-only group (p < 0.001).

The authors commented that because patients with MRD-negative remission have a better prognosis than those with MRD-positive remission, an intentional prolonged follow-up was necessary to have enough events to show a benefit with regard to OS.

Studies currently in development are exploring the use of blinatumomab earlier in the course of disease, including a trial of blinatumomab alternating with low-intensity chemotherapy as compared with standard-of-care chemotherapy among older adults with newly diagnosed BCR::ABL1-negative disease.

The study was supported by grants from the NCI and National Institute of General Medical Sciences of the National Institutes of Health, the Canadian Cancer Society and in part by Amgen.

Reference

Litzow MR, Sun Z, Mattison RJ, et al. Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults. N Engl J Med 2024;391:320-333.

 

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