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Amgen to Seek Blincyto Approval in MRD-Negative ALL Following Positive Phase III Results


NEW YORK – Amgen is seeking regulatory approval for Blincyto (blinatumomab) for patients with newly diagnosed B-lineage acute lymphoblastic leukemia patients with no detectable minimal residual disease based on activity seen in a Phase III trial.

Mark Litzow, a hematology oncologist at the Mayo Clinic, presented data from the registration-directed, randomized, Phase III ECOG-ACRIN E1910 trial at the American Society of Hematology's annual meeting on Tuesday. "We believe that these results represent a new standard of care for this group of MRD-negative patients," Litzow said.

The bispecific T-cell engager (BiTe) antibody Blincyto is designed to attach simultaneously to CD19 antigens on the surface of cancer cells and CD3 on T cells, which trains cytotoxic T cells to attack the tumor cells.

The agent is already approved in the US and other countries for minimal residual disease (MRD)-positive, CD19-expressing ALL patients. The drug's US Food and Drug Administration-approved label specifies patients' cancers must be in first or second complete remission but with MRD greater than or equal to 0.1 percent. The drug is also approved for relapsed or refractory CD19-positive B-cell precursor ALL.

Now, following the latest positive data, a spokesperson from Amgen said that the company is preparing regulatory submissions in collaboration with the study sponsors, including the National Cancer Institute and the ECOG-ACRIN (Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network) Cancer Research Group. Amgen said it's too early to speculate on the timing of submissions and FDA's response, but said the data will be shared with regulators "in due course."

Through this randomized, Phase III trial, Litzow and colleagues wanted to see whether patients might benefit from treatment with the BiTe antibody even if their cancers were in complete remission without any detectable MRD.

"We know that even though we can't find leukemia in these patients' bone marrow, it's still hiding there, and they can often relapse during their treatment," Litzow said.

To be eligible for the trial, patients had to have Philadelphia chromosome-negative B-lineage ALL; they were additionally screened at the outset for BCR-ABL translocations and had to be negative. This screening was done through conventional cytogenetics, fluorescence in situ hybridization, and/or PCR testing on baseline bone marrow and peripheral blood samples. If patients were biomarker negative via conventional cytogenetics, they also had to undergo FISH or PCR testing to rule out occult translocations.

After determining eligibility, patients first received induction therapy to induce remission. Only patients whose cancers entered complete remission or complete remission with incomplete count recovery after induction therapy proceeded to the next step. These patients then received another round of intensive chemotherapy administered to the central nervous system to ensure they had no leukemia cells present there.

Following these initial rounds of chemo, patients underwent MRD testing using a six-color flow cytometry panel performed centrally at the ECOG-ACRIN Leukemia Translational Research Laboratory. Only then did patients who had no detectable MRD — defined as MRD equal to or less than 0.1 percent of leukemia cells — proceed onto the randomization step.

In total, 224 patients were randomized to receive either Blincyto and consolidation chemotherapy or consolidation chemotherapy alone.

After their respective randomized treatments, patients on both trial arms went onto receive maintenance chemotherapy. However, patients were also able to receive a bone marrow transplant after Blincyto treatment instead of consolidation and maintenance therapy at their doctors' discretion. Of the 224 MRD-negative patients, 22 in each arm went onto receive a transplant.

The full course of therapy took about 2.5 years, Litzow said.

As for patients who tested positive for MRD, Litzow said they were directly assigned to receive the chemo and Blincyto combination instead of being randomized. This wasn't the original plan, but the trial was adapted after the FDA approved Blincyto for MRD-positive, CD19-expressing ALL patients in 2018.

"When the trial was first designed, we'd planned to randomize the MRD-positive patients as well, but in March 2018, the FDA approved blinatumomab for MRD-positive patients based on a European trial," Litzow said. "When that came about, we assigned the patients who were MRD-positive at that time point to get the blinatumomab plus chemotherapy."

Overall survival gains

As of September 2022, members of the ECOG-ACRIN data safety monitoring committee recommended that the results be released, given that in MRD-negative patients, the results clearly favored Blincyto plus chemo. After a median follow-up of 43 months, patients who received chemotherapy alone lived for a median of 71.4 months. In the Blincyto combination arm, meanwhile, the median overall survival time was not yet reached. The relapse-free survival time was also better in the combination arm; patients receiving chemo lived for a median of 22.4 months without their cancers relapsing, whereas this median time was not reached for patients who received Blincyto and chemotherapy.

"We hope that this means patients will continue to remain in remission and be cured," Litzow said. "We feel that this should be incorporated into their standard therapy."

Litzow pointed out that, based on the efficacy seen with Blincyto, it could end up replacing allogeneic bone marrow transplants in MRD-negative patients, since "it's pretty hard to beat this [Blincyto] survival curve with a transplant." Given the intensive nature of bone marrow transplants — which carry significant safety risks, including the risk of developing graft-versus-host disease — Litzow said this would be welcome news. Among patients receiving the Blincyto-chemo combination in the ECOG-ACRIN study, on the other hand, Litzow said the regimen was generally well tolerated with no new safety signals.

"We will see diminishing use of transplant in this setting because of these results," he said, calling this possibility a "big plus."