Blinatumomab Approval Expanded Based on MRD

When the FDA expanded the approval of blinatumomab (Blincyto; Amgen) in March to include a broader population of adults and children with B-cell precursor acute lymphoblastic leukemia (ALL), the agency did so using minimal residual disease (MRD) as a regulatory endpoint: It based the approval on results of the phase II BLAST trial, in which MRD was undetectable in 81% of patients treated with the drug. This is the first time MRD has been used as the primary endpoint for an approval of a drug to treat ALL, and as such may signal more MRD-based approvals to come.

MRD refers to small numbers of leukemia cells still present in a patient's bone marrow during or after treatment that cannot be detected under a microscope, but can cause a relapse. According to Lia Gore, MD, of the University of Colorado Anschutz Medical Campus and Children's Hospital Colorado, both in Aurora, MRD testing was developed as a research tool. In the early 2000s, as more sophisticated flow cytometry and PCR technologies improved the test's sensitivity, clinicians began recognizing its value for predicting patient response.

“We have been able to determine that MRD is a more sensitive, better way to mark disease status than our prior methods,” she says. Although the FDA has not previously used MRD as a regulatory endpoint for ALL, “in the clinical community, we all think MRD really counts,” she adds. “That's where the bang for the buck is. If you can get somebody to an MRD negative state, that is the best potential response.”

She thinks the recent FDA approval of blinatumomab based on MRD could pave the way for other such approvals: “Overall it gives us a sense that this is really the direction that we're probably going, and we should think a lot about what the predictive value is in these circumstances, so we can really be prepared to design our clinical trials appropriately.”

Steven Hunger, MD, of Children's Hospital of Philadelphia, PA, notes that for MRD to become useful as a major endpoint, trials must continue to show that it translates into a survival benefit for patients, as was shown in the BLAST trial. He points out that this survival benefit has already been established for chronic myeloid leukemia, where major molecular response, a measure similar to MRD, is used for approvals.

The BLAST trial enrolled patients with ALL who were in their first or second remission and had an MRD of at least one leukemia cell per 1,000 bone-marrow cells. In total, 70 of 86 patients treated with blinatumomab, a bispecific T-cell engager that directs T cells to kill malignant B cells, achieved the primary endpoint of undetectable MRD, or less than one leukemia cell per 10,000 cells. Patients with a complete MRD response had a median relapse-free survival of 23.6 months, compared with 5.7 months in patients who did not have an MRD response.

The drug, now approved for patients with ALL who are in remission but still have MRD, was previously approved to treat adults and children with relapsed or refractory ALL.

Hunger and Gore expect the drug to be particularly useful as a “bridge to transplant” for patients with ALL who are MRD positive: These patients often can be cured only with a stem-cell transplant, but the procedure is unlikely to be successful unless patients are MRD negative.

“I think this could be very impactful for patients,” Hunger says. “Presumably now a patient who is MRD positive could get blinatumomab outside the context of a clinical trial and have the drug covered by his or her insurance.” –Catherine Caruso