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Blinatumomab Improves Survival in MRD-Negative, B-Cell ALL


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The standard of care could be changing for adults with newly diagnosed BCR-ABL–negative B-lineage acute lymphoblastic leukemia (ALL) who achieve measurable residual disease (MRD) negativity after induction chemotherapy. In the phase III E1910 trial by the ECOG-ACRIN Cancer Research Group, an overall survival benefit was derived with the addition of blinatumomab to consolidation chemotherapy, suggesting that even this lower-risk subset of patients may benefit from this bispecific antibody.1 The results were presented as a late-breaking abstract at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition by Mark R. Litzow, MD, Professor of Medicine at the Mayo Clinic, Rochester, Minnesota.


“This trial … showed for the first time an overall survival advantage for adult patients with MRD-negative, BCR-ABL–negative, B-lineage ALL who receive blinatumomab combined with chemotherapy.”
— Mark R. Litzow, MD

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Blinatumomab given as part of consolidation chemotherapy led to a 58% reduction in the risk of death compared with chemotherapy alone. Median overall survival with blinatumomab plus chemotherapy was not reached, as compared with 71.4 months with chemotherapy alone (hazard ratio [HR] = 0.42; P = .003).

“This trial, E1910, showed for the first time an overall survival advantage for adult patients with MRD-negative, BCR-ABL–negative, B-lineage ALL who receive blinatumomab combined with chemotherapy,” Dr. Litzow said. “We feel this represents a new standard of care for this group of patients and should be incorporated into their standard therapy.”

“I think these results suggest that fewer of these patients will need a stem cell transplant. The overall survival curve we saw—it’s pretty hard to beat that with a transplant.”
— Mark R. Litzow, MD

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He continued: “Blinatumomab has not been studied or approved in MRD-negative patients, and that is the purpose of this study. If patients achieve MRD negativity, they’re in a better category [than MRD-positive] and have a better prognosis, but they can still have recurrence of their leukemia…. I think these results suggest that fewer of these patients will need a stem cell transplant. The overall survival curve we saw—it’s pretty hard to beat that with a transplant.” Based on the efficacy shown in MRD-negative patients, the data safety monitoring committee recommended the trial be halted and the results released after a median follow-up of 3.6 years.

Blinatumomab is designed to direct cytotoxic T cells to CD19-expressing cancer cells. The agent is currently approved for use in adult and pediatric patients with B-cell precursor ALL who are in remission but are still MRD-positive, as well as in adult and pediatric patients with relapsed or refractory disease.

About ECOG-ACRIN E1910

In the phase III ECOG-ACRIN E1910 trial, 488 patients underwent standard induction chemotherapy for 2.5 months using a Berlin-Frankfurt-Muenster (BFM)-like induction regimen modified from the E2993/UKALLXII protocol.2 The patients achieving a complete response or complete response with incomplete recovery then received 1 month of intensification therapy with high-dose methotrexate and pegaspargase (for protection of the central nervous system).

MRD status was assessed, with MRD negativity defined as less than 0.01% ALL cells. Initially, MRD-positive patients were also randomly assigned, but following approval of blinatumomab by the U.S. Food and Drug Administration (FDA) in 2018, MRD-positive patients were all assigned to the blinatumomab/chemotherapy arm.

Of the 488 enrolled patients, 395 (81%) achieved a complete response or complete response with incomplete recovery. Ultimately, a total of 286 patients were randomly assigned, including 224 who were MRD-negative and 62 who were MRD-positive (22 randomly assigned, 40 not randomly assigned).

KEY POINTS

  • In patients with BCR-ABL-negative ALL who achieve MRD negativity after consolidation chemotherapy, the addition of blinatumomab to consolidation chemotherapy improved overall survival: median was not reached with blinatumomab vs 71.4 months with chemotherapy alone (HR = 0.42; P = .003).
  • A small subset of MRD-positive patients also derived a numeric benefit in overall survival from blinatumomab; median overall survival was not reached in that arm vs 22.4 months with chemotherapy alone (HR = 0.39; P = .06).
  • Blinatumomab given with consolidation chemotherapy may become a new standard of care in this better-prognosis subset.

Patients were randomly assigned 1:1 to receive consolidation chemotherapy (in four monthly cycles [n = 112]) or the same with blinatumomab (monthly combination consolidation chemotherapy interspersed with monthly cycles of blinatumomab by continuous infusion, including two cycles of blinatumomab followed by three cycles of chemotherapy followed by another cycle of blinatumomab, then another chemotherapy cycle, then a final cycle of blinatumomab [n = 112]). All patients received maintenance chemotherapy for approximately 2.5 years, timed from the start of intensification.

“The intent was for patients in both arms to have an equal duration of therapy,” he said. “Nearly 60% of patients received all four cycles of blinatumomab, and 80% received at least two.” There were 22 patients who, at their physician’s discretion, underwent allogeneic stem cell transplantation. The primary endpoint was overall survival in the MRD-negative patients, using a significance level of .025.

Robust Outcomes

In MRD-negative patients, median overall survival was not reached in the blinatumomab arm and was 71.4 months with combination chemotherapy alone (HR = 0.42; P = .003). At 3.6 years, 83% of the blinatumomab arm were alive vs 65% in the chemotherapy group. There were 17 deaths on the blinatumomab arm (8 due to relapse, 9 due to nonrelapse causes) vs 39 on the chemotherapy-alone arm (20 due to relapse, 17 due to nonrelapse causes, and 2 from unknown causes), Dr. Litzow reported. “I want to point out that for overall survival, time zero is from randomization, not from the time of study entry or diagnosis,” he said.

Dr. Litzow also reported outcomes for MRD-positive patients, which included 40 patients treated with blinatumomab plus chemotherapy and 22 originally assigned to treatment with chemotherapy alone. Again, median overall survival was not reached in the blinatumomab arm and was 22.4 months with chemotherapy alone (HR = 0.39; 95% confidence interval = 0.14–1.10; P = .06). Although the Kaplan-Meier curves virtually mirror those of the primary analysis, he pointed out that the hazard ratio crosses 1, and the P value for this secondary endpoint is not significant.

The combination of blinatumomab and chemotherapy was generally well tolerated, with no new safety signals reported. 

DISCLOSURE: Dr. Litzow reported financial relationships with Jazz and BioSight.

REFERENCES

1. Litzow MR, Sun Z, Paletta E, et al: Consolidation therapy with blinatumomab improves overall survival in newly diagnosed adult patients with B-lineage acute lymphoblastic leukemia in measurable residual disease negative remission: Results from the ECOG-ACRIN E1910 randomized phase III National Cooperative Clinical Trials Network trial. 2022 ASH Annual Meeting and Exposition. Abstract LBA1. Presented December 13, 2022.

2. Rowe JM, Buck G, Burnett AK, et al: Induction therapy for adults with acute lymphoblastic leukemia: Results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 106:3760-3767, 2005.


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