Adding a Bi-Specific T-Cell Engager Brings Striking Benefit in Childhood Acute Lymphoblastic Leukemia

Audio Journal of Oncology Podcast

SAN DIEGO, USA—When added to standard chemotherapy the bi-specific T-cell engager drug blinatumomab brought a large, statistically significant improvement in disease-free survival in a randomized controlled study of 1731 children with average or higher relapse-risk B-cell acute lymphoblastic leukemia.

Study first author Rachel E. Rau MD, from the Seattle Children’s Hospital, University of Washington, in the USA, reported her group’s findings at the 2024 Annual Meeting of the American Society of Hematology in San Diego. Hot from the conference she gave the details to Audio Journal of Oncology reporter, Peter Goodwin:

Audio Journal of Oncology PODCAST EPISODE:

Rachel E. Rau MD, Seattle Children’s Hospital, University of Washington, USA.

IN: Rachel Rau, you’re with me on-line now ……

OUT: …..Journal of Onclogy, I’m Peter Goodwin. Thank you Peter, it’s a pleasure.

Duration: 13:06

ABSTRACT:

https://ash.confex.com/ash/2024/webprogram/Paper207450.html

Title:

Blinatumomab Added to Chemotherapy Improves Disease-Free Survival in Newly Diagnosed NCI Standard Risk Pediatric B-Acute Lymphoblastic Leukemia: Results from the Randomized Children’s Oncology Group Study AALL1731

ASH 2024 Presenting Author:

Rachel E. Rau, MD1,

Seattle Children’s Hospital, University of Washington, Seattle, WA

Introduction:

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Children with newly-diagnosed, National Cancer Institute (NCI) standard risk (SR) B-ALL have high survival rates when treated with traditional chemotherapy (chemo), yet some relapse and die. Relapsed ALL is a leading cause of pediatric cancer mortality and about half of relapses occur in SR B-ALL. AALL1731 (NCT03914625) is a phase 3 randomized trial to determine if 2 non-sequential cycles of the bi-specific T-cell engager blinatumomab (15 mg/m2/day IV continuous x 28 days) added to chemo improves disease-free survival (DFS) in children with NCI SR B-ALL with average or higher relapse risk.

Methods:

AALL1731 enrolled newly diagnosed NCI SR (age >1 and <10 years with initial white blood cell count (WBC) <50,000/uL) B-ALL patients (pts), BCR::ABL1 negative, without testicular or CNS3 disease. After a 3-drug induction, pts were assigned to 3 risk groups based on tumor genetics, CNS status, and multiparameter flow cytometry (mpFC) defined minimal residual disease (MRD) at induction day 8 in peripheral blood (PB) and end of induction (EOI) in bone marrow (BM). Pts with favorable cytogenetics [ETV6::RUNX1 or double trisomies of chromosomes 4 and 10 (DT)], day 8 PB mpFC MRD <1% and EOI BM mpFC MRD <0.01% were categorized as SR-Favorable and non-randomly received chemo alone given known outstanding outcomes. Pts with unfavorable cytogenetics (iAMP21, KMT2A rearrangement, t(17;19), hypodiploidy), EOI mpFC MRD ?0.1% for DT and ?0.01% all others, or neutral cytogenetics with CNS2 status were categorized as SR-High. All others were considered SR-Average (Avg).

SR-Avg pts were further stratified based on EOI BM high-throughput sequencing of immunoglobulin loci (HTS) MRD. Those with undetectable EOI HTS MRD were non-randomly assigned to standard-intensity chemo alone (Arm A); all others were randomized to Arm A or standard-intensity chemo plus 2 cycles of blinatumomab (Arm B).

Post induction, SR-High pts received augmented BFM-based chemo. SR-High pts with end consolidation BM mpFC MRD <0.1% were randomized to chemo (Arm C) or chemo plus 2 cycles of blinatumomab (Arm D). Blinatumomab cycles were inserted before and after interim maintenance I. Planned accrual included 2245 pts with a minimum follow-up (FU) of 3 years.

Results:

Accrual began June 28, 2019. At the first planned interim efficacy analysis (data cutoff June 30, 2024), 1440 (63%) of the 2245 SR-Avg/SR-High eligible and evaluable pts had been randomized. Median age was 4.3 years [interquartile range (IQR) 2.8-6.4]; 52.6% were boys, 26% were Hispanic and 5% were non-Hispanic Black. Median FU was 2.5 years (IQR=1.6-3.2). 722 pts were randomized to control Arms A (418) and C (304), and 718 to blinatumomab Arms B (417) and D (301). In intent-to-treat analyses, the 3-year DFS (± standard error) was 96.0±1.2% for pts randomized to blinatumomab arms vs 87.9±2.1% for those randomized to control arms. Using a stratified log-rank test, adding blinatumomab significantly improved DFS [Hazard Ratio (HR) 0.39, 95% confidence interval (CI) 0.24-0.64, 1-sided p<0.0001], substantially exceeding pre-specified interim efficacy stopping criteria and prompting the COG data safety and monitoring committee to recommend early termination of randomization.

Among SR-Avg patients, 3-year DFS for Arm B (blinatumomab) was 97.5±1.3% vs 90.2±2.3% for Arm A (control) (HR 0.33, 95%CI 0.15-0.69). For SR-High patients, 3-year DFS was 94.1±2.5% for Arm D (blinatumomab) vs 84.8±3.8% for Arm C (control) (HR 0.45, 95%CI 0.24-0.85). Overall, there were 6 deaths in remission, all among SR-High pts (Arm C=2, Arm D=4), none during blinatumomab cycles. Of 56 relapses on control arms, 10 were isolated CNS (iCNS), 34 isolated BM (iBM) and 5 combined CNS/BM. Of 19 relapses on blinatumomab arms, 9 were iCNS, 9 iBM, and 1 combined. Blinatumomab was well tolerated, with 0.3% of first courses associated with Grade 3+ cytokine release syndrome and 0.7% with seizures.

Conclusions:

This randomized clinical trial definitively establishes that adding blinatumomab to chemo significantly improves DFS in newly diagnosed childhood SR B-ALL, both of average and higher risk, resulting in outcomes similar to those previously achieved in only the most favorable risk subsets. The addition of blinatumomab represents a major breakthrough and is a new treatment standard, with implications for children with newly-diagnosed B-ALL.