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SAN DIEGO -- Children with newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL) lived significantly longer without disease recurrence when they received the bispecific T-cell engager blinatumomab (Blincyto) in addition to chemotherapy, according to a randomized trial reported here.

Median disease-free survival (DFS) at 3 years improved from 87.9% with chemotherapy alone to 96.0% with the blinatumomab consolidation. DFS improved significantly in patients with a National Cancer Institute (NCI)-defined standard risk of relapse, including standard risk-average and standard risk-high. In the overall population, the absolute difference translated into a 61% reduction in the hazard ratio for disease recurrence, and the benefit was consistent across prespecified subgroups.

Major adverse events (AEs) were uncommon, but average-risk patients assigned to blinatumomab did have a higher rate of nonfatal sepsis and catheter-related infections, reported Rachel E. Rau, MD, of the University of Washington and Seattle Children's Hospital, at the American Society of Hematology meeting.

"The results of our very first efficacy interim analysis demonstrated that, in fact, blinatumomab does improve disease-free survival," Rau said during a press briefing. "The improvement in disease-free survival was secondary to a significant reduction in bone marrow relapses .... We did not see a similar reduction in the more rare event of an isolated central nervous system [CNS] relapse. This was not surprising, given blinatumomab's known limited activity in the central nervous system."

"Overall, our results demonstrated that blinatumomab added to chemotherapy represents a new treatment standard for most patients with NCI standard-risk B-cell ALL," she added.

Co-principal investigator Sumit Gupta, MD, PhD, of the Hospital for Sick Children in Seattle, said in a statement, "These breakthrough data showing a significant improvement in disease-free survival are set to bring a tremendous clinical benefit to nearly all children with newly diagnosed B-ALL. This is changing the standard of care for children with B-ALL around the world."

The results were published simultaneously in the .

Challenges to Access

Without minimizing the significance of the results, press briefing moderator Ariela Marshall, MD, of the University of Minnesota in Minneapolis, noted that "this therapy might have significant barriers to access, including cost and the infusion needs. Given these barriers, how do you see this therapy fitting into the real world? Is it something truly accessible to patients and their families?"

Rau acknowledged that "if we can't get blinatumomab to every patient who might benefit from it, then I think we've fallen short of our goals."

With regard to access, the FDA "somewhat fortuitously" for all patients 1 month and older with B-ALL just shortly before the study results were released. The approval does not address the access issues posed by a medication administered by continuous infusion.

"It's particularly hard to give a continuously infused medication to someone who lives really far from a medical center," said Rau.

She suggested two potential ways to overcome the administration issue. One related to ongoing evaluation of subcutaneously delivered formulations of blinatumomab. Additionally, similar, longer-acting drugs are under development.

With regard to the issue of global access to the drug, Rau said "That's a much more challenging portion of this to tackle, and I don't think any of us have the best answers for that. We're all focused on finding ways to make it accessible to everyone globally, not just in well-developed countries."

Accumulation of Evidence

Blinatumomab targets CD19 expressed on the surface of B cells and redirects CD3+ T cells for CD19-selective lysis. Rau reported results from the multicenter trial, which followed other positive studies, including the trial of adults with advanced ALL; the BLAST trial in adults and children with B-ALL in first or second remission, which led to ; a phase II study in newly diagnosed Philadelphia chromosome-negative B-ALL; a phase III study of consolidation therapy for measurable residual disease (MRD)-negative B-ALL; and a small phase II study of sequential treatment for aggressive pediatric B-ALL.

AALL1731 involved 1,440 children (median age at randomization of 4.3 years) with standard-risk B-ALL, enrolled at sites in the U.S., Canada, Australia, and New Zealand. Patients were stratified by NCI criteria into standard risk-average (N=835) and standard risk-high (N=605) categories. Randomized treatment consisted of a standard three-drug chemotherapy regimen with or without two cycles of blinatumomab consolidation. The primary endpoint was DFS.

After a median follow-up of 2.5 years, the trial met the primary endpoint, showing a statistically significant reduction in DFS in the patients who received blinatumomab. Statistically significant differences were observed in the overall population (HR 0.39, P<0.0001), the standard-average risk subgroup (97.5% vs 90.2%, HR 0.33, P=0.0019), and standard-high risk subgroup (94.1% vs 84.8%, HR 0.45, P=0.0126).

The DFS benefit held up in a subgroup analysis that included risk categories, sex, race/ethnicity, cytogenetics status (favorable, neutral, unfavorable), and MRD status.

The overall difference between treatment groups was driven by a reduction in bone marrow relapses (P<0.0001). The frequency of CNS relapse did not differ between treatment groups (P=0.8510).

Blinatumomab target toxicities (cytokine release syndrome, seizure, and encephalopathy) were infrequent and decreased from cycle 1 (4.5% grade 2, 1.3% grade 3) to cycle 2 (2.5%, 0.7%). Grade ≥3 infections occurred more often in standard risk-average patients with the addition of blinatumomab to chemotherapy, including febrile neutropenia (39.6% vs 47.0%, P=0.05) and sepsis and catheter-related infections (5.1% vs 14.8%, P<0.001). Infectious toxicities occurred with similar frequency in the standard risk-high subgroup.

With respect to the difference in infectious toxicities in the standard risk-average patients, Rau and co-authors noted in the journal article that "this result was not attributable to infectious events occurring during blinatumomab cycles; these adverse events occurred instead in subsequent treatment cycles (e.g., during delayed intensification of chemotherapy)."