Blinatumomab Plus Consolidation Chemo Prolongs Overall Survival in MRD-Negative B-Cell Precursor ALL

Blinatumomab Plus Consolidation Chemo Prolongs Overall Survival in MRD-Negative B-Cell Precursor ALL

Blinatumomab (Blincyto) plus consolidation chemotherapy provided a significant overall survival (OS) benefit vs consolidation chemotherapy alone in patients with minimal residual disease (MRD)–negative B-cell precursor acute lymphoblastic leukemia (ALL), as demonstrated in findings from the phase 3 ECOG-ACRIN E1910 trial (NCT02003222) published in the New England Journal of Medicine.¹

At a median follow-up of 43 months, findings from the third interim efficacy analysis of E1910 demonstrated that MRD-negative patients who received the bispecific T-cell engager (n = 112) achieved a 3-year OS rate of 85% compared with 68% among patients who received consolidation chemotherapy alone (n = 112; HR, 0.41; 95% CI, 0.23-0.73; P = .002). The relapse-free survival (RFS) rates were 80% vs 64%, respectively (HR, 0.53; 95% CI, 0.32-0.87).

“[This patient population] has traditionally had a better prognosis with chemotherapy than patients who are MRD positive after induction chemotherapy, but many of them can still relapse,” Mark R. Litzow, MD, lead study author and a professor of medicine (now retired) at the Mayo Clinic in Rochester, Minnesota, explained in an interview with our sister publication, OncLive®. “We wanted to see if adding blinatumomab to their chemotherapy regimen would go after any leukemia cells that were remaining that we weren’t detecting, [thus] improving their survival. Indeed, we found that adding blinatumomab to the chemotherapy regimen did lessen their risk of relapse and improve their survival. We believe this is a new standard of care.”

On June 14, 2024, blinatumomab was granted approval by the FDA for the treatment of adult and pediatric patients aged 1 month or older with CD19-positive, Philadelphia chromosome (Ph)–negative, B-cell precursor ALL in the consolidation phase, regardless of MRD status. The regulatory decision was supported by preliminary findings from E1910.^2,3

E1910 enrolled patients who were 30 to 70 years of age with BCR::ABL1-negative B-cell precursor ALL who achieved MRD-negative remission, defined as less than 0.01% leukemic cells in the bone marrow per flow cytometry after induction and intensification chemotherapy. Patients were randomly assigned to receive 4 cycles of chemotherapy plus 4 cycles of blinatumomab. Blinatumomab was administered at a dose of 28 μg per day for 4 weeks, with a 2-week interval between cycles, followed by 4 cycles of chemotherapy and 2 additional cycles of blinatumomab, or 4 cycles of consolidation chemotherapy only. Stratification occurred based on patient age (30 to 54 years or ≥ 55 years), CD20 status (positive or negative), rituximab (Rituxan) use (yes or no), and whether transplantation was intended (yes or no).¹

The primary end point was OS in the MRD-negative subgroup. RFS represented a secondary end point.

At baseline, the median age was 51.5 years (range, 30-69) vs 50 years (range, 30-70) in the combination and chemotherapy-only arms, respectively. Most patients in both arms had an ECOG performance status of 1 or less (95% vs 90%), did not intend to undergo transplantation at random assignment (68% vs 69%), and had a CD10-positive, early pre-B immunophenotype (85% vs 83%). Patients in both arms had favorable (17% vs 26%), intermediate (20% vs 17%), unfavorable (45% vs 39%), and no risk assigned (19% vs 18%) combined risk disease.

Additional findings from a multivariable analysis of E1910 adjusting for sex, white cell count, platelet count, hemoglobin level, peripheral blood blasts, bone marrow blasts, ECOG performance status, and combined molecular risk category revealed that the addition of blinatumomab to consolidation chemotherapy reduced the risk of death vs consolidation chemotherapy alone by 56% (HR, 0.44; 95% CI, 0.23-0.81). The addition of blinatumomab also offered a significant RFS benefit vs chemotherapy alone (HR, 0.57; 95% CI, 0.33-0.98).

Among patients who were younger than 55 years old (n = 132), significant OS (HR, 0.16; 95% CI, 0.05-0.47) and RFS (HR, 0.31; 95% CI, 0.14- 0.69) benefits were observed with the addition of blinatumomab. Similarly, patients 55 years of age or older (n = 93) also experienced OS (HR, 0.66; 95% CI, 0.33-1.35) and RFS (HR, 0.74; 95% CI, 0.39-1.43) benefits when blinatumomab was added to consolidation chemotherapy.

“E1910 is the first randomized trial to demonstrate that we are able to improve the survival of adults with B-cell precursor ALL who are in complete remission, including by sensitive MRD testing, and establishes the addition of blinatumomab immunotherapy to standard consolidation chemotherapy as a treatment that will change clinical practice,” Selina M. Luger MD, FRCPC, study coauthor and chair of the ECOG-ACRIN Leukemia Committee, as well as a professor of medicine (Hematology-Oncology) at the Hospital of the University of Pennsylvania, in Philadelphia, said in a press release.²

In terms of safety, grade 3, 4, and 5 nonhematologic treatment-related adverse effects (TRAEs) occurred at rates of 43%, 14%, and 2%, respectively, among patients in the blinatumomab arm. These TRAEs were reported at rates of 36%, 15%, and 1%, respectively, in the control arm (P =.17). Grade 3 anemia (20% vs 35%), febrile neutropenia (16% vs 21%), and thrombocytopenia (9% vs 10%) were present in both the investigational and control arms, respectively.

“We’re going to be [examining] incorporating blinatumomab earlier into treatment,” Litzow said. “I believe we may also be able to reduce the amount of chemotherapy patients receive given the efficacy of [agents such as blinatumomab]. We are going to see a greater use of these agents and lessening the use of chemotherapy. But we have to be cautious in doing this because we don’t want to make dramatic changes and then find out that they necessarily don’t work. [However], the general trend will be to make greater use of these agents.”

References

1. 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. doi:10.1056/NEJMoa2312948
2. New England Journal of Medicine publishes outcomes from practice-changing E1910 trial for patients with BCR::ABL1-negative B-cell precursor acute lymphoblastic leukemia. News release. ECOG-ACRIN Research Group. July 24, 2024. Accessed July 24, 2024. https://www.eurekalert.org/news-releases/1051981
3. FDA approves Blincyto (blinatumomab) in CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (B-ALL) in the consolidation phase. News release. Amgen. June 14, 2024. Accessed July 24, 2024. https://www.amgen.com/newsroom/press-releases/2024/06/fda-approves-blincyto-blinatumomab-in-cd19positive-philadelphia-chromosomenegative-bcell-precursor-acute-lymphoblastic-leukemia-ball-in-the-consolidation-phase