‘Blin’-ing Is Winning for Children With B-Cell Acute Lymphoblastic Leukemia

Although survival of children with acute lymphoblastic leukemia (ALL) has dramatically improved over the past two decades,¹  those with National Cancer Institute (NCI) standard-risk (SR) B-cell acute lymphoblastic leukemia (B-ALL) still account for half of all pediatric ALL relapses,^2,3  the five-year overall survival (OS) rate of which remains poor at 38%.³  These outcomes are anticipated to improve appreciably with intercalation of new frontline immunotherapeutic approaches based on remarkable recent clinical trial data across the age spectrum of infant to older adult that represents one of the greatest breakthroughs in ALL therapy.

Blinatumomab is a bispecific antibody that directs CD3⁺ host T cells against CD19⁺ B-lineage ALL cells, causing selective lysis of the latter. This immunotherapy was shown to be more effective than chemotherapy in adults with relapsed/refractory (R/R) Philadelphia chromosome (Ph)-negative B-ALL,⁴  leading to its initial approval by the U.S. Food and Drug Administration (FDA) in 2014. When added to upfront chemotherapy in adults, blinatumomab improved survival regardless of minimal residual disease (MRD) status, including for those in complete remission.^5,6  Blinatumomab has also been highly effective in combination with the tyrosine kinase inhibitors dasatinib or ponatinib as a “chemotherapy-free” regimen for patients with BCR::ABL1-rearranged (Ph+) B-ALL.^7-9  On June 14, 2024, based on recent and emerging pediatric-specific data, the FDA extended its approval of blinatumomab to all patients with CD19-positive Ph-negative B-ALL over one month of age.

Blinatumomab was previously reported to be both safe and effective in children and adolescents/young adults with R/R B-ALL.^10-12  In comparison to standard relapse chemotherapy alone, blinatumomab demonstrated superior results in two separate randomized phase Ill clinical trials for pediatric patients with first relapse of B-ALL. In the 20120215 (NCT02393859) study, blinatumomab was associated with improved event-free survival (EFS) (69% vs. 43% at median follow-up of 22.4 months),¹¹  increased MRD remission (90% vs. 54%),¹¹  and higher rates of hematopoietic stem cell transplantation (HSCT) (89% vs. 70%).¹¹  In the Children’s Oncology Group (COG) AALL1331 (NCT02101853) study, the use of blinatumomab resulted in increased MRD remission (75% vs. 32%),¹²  higher rates of HSCT (70% vs. 43%),¹²  and improved two-year OS (71% vs 58%).¹²  An Interfant group pilot study investigating the addition of post-induction blinatumomab for infants with newly-diagnosed CD19+ KMT2A-rearranged B-ALL also demonstrated a remarkable improvement in two-year disease-free survival (DFS) of 81.6% (95% CI 60.8-92.0) and OS of 93.3% (95% CI 75.9-98.3)¹³  for a population with historically dismal survival rates (EFS, 42.4%; OS, 54.5%).^14,15 

COG AALL1731 (NCT03914625) is a phase III randomized trial that investigated the addition of two non-sequential blinatumomab cycles (15 mg/m²/day IV continuously for 28 days per cycle) added to a standard multi-agent chemotherapy in children with Ph-negative NCI SR B-ALL (age >1 and <10 years with initial white blood cell count <50,000/uL) without testicular or central nervous system (CNS)-3 status.¹⁶  The study opened on July 3, 2019, and its first planned interim efficacy analysis was recently performed (data cutoff: June 30, 2024), at which time 1,440 (63%) of eligible evaluable subjects had been randomized (chemotherapy alone, n=722; chemotherapy + blinatumomab, n=718). After a three-drug induction, patients were assigned to one of three risk groups based on leukemia genetics, CNS status, induction day 8 peripheral blood MRD by flow cytometry (FC), and end-of-induction day 29 bone marrow MRD by FC and next-generation sequencing (NGS). Children at lowest risk of relapse (SR-favorable) subsequently received post-induction chemotherapy alone, while those with SR-average-risk stratification and detectable NGS MRD were randomized to standard-intensity chemotherapy alone or with blinatumomab (arms A and B, respectively). Patients with SR-high-risk stratification due to unfavorable ALL-associated genetics or end-of-induction MRD positivity received augmented consolidation chemotherapy, while those with end-consolidation marrow FC MRD less than 0.1% were randomized to chemotherapy alone or with blinatumomab (arms C and D, respectively) following consolidation and interim maintenance I.

In December 2024, Rachel E. Rau, MD, and Sumit Gupta, PhD, and their colleagues presented groundbreaking AALL1731 results at the American Society of Hematology’s annual meeting.¹⁷  In intent-to-treat analyses, the three-year DFS (± standard error) was 96.0±1.2% for blinatumomab-treated patients versus 87.9±2.1% for chemotherapy alone. The addition of blinatumomab significantly improved DFS (hazard ratio [HR] = 0.39, 95% CI 0.24-0.64, one-sided p<0.0001) and substantially exceeded the study’s prespecified interim efficacy stopping criteria, prompting early termination of patient randomization. Among SR-average patients, three-year DFS for blinatumomab/arm B was 97.5±1.3% versus 90.2±2.3% for chemotherapy alone/arm A (HR=0.33, 95%CI 0.15-0.69). For SR-high patients, three-year DFS was 94.1±2.5% for blinatumomab/arm D versus 84.8±3.8% for chemotherapy alone/arm C (HR=0.45, 95%CI 0.24-0.85). Blinatumomab therapy was extremely well-tolerated, with 0.3% of courses associated with grade 3 or higher cytokine release syndrome and 0.7% with seizures (also seen in eight out of 47 [17%] of children with Down syndrome-associated B-ALL treated non-randomly with blinatumomab in a separate cohort of the AALL1731 trial).¹⁸  Death in remission occurred in six patients with SR-high B-ALL (arm C, n=2; arm D, n=4), but there were no deaths during blinatumomab cycles. Fifty-six patients in the chemotherapy arms A and C subsequently relapsed (10 isolated CNS [iCNS], 34 bone marrow [BM], five combined CNS/BM) compared to 19 relapses in the blinatumomab arms B and D (nine iCNS, nine BM, one combined CNS/BM).

Based on the remarkable AALL1731 and adult E1910 data,^6,19  with both demonstrating clear superiority of blinatumomab-based therapy, the COG halted its AALL1732 phase III randomized study of chemotherapy versus chemotherapy plus inotuzumab for pediatric patients with high-risk B-ALL (NCT03959085), recommending that these subjects also receive two non-sequential blocks of blinatumomab intercalated with chemotherapy. This recommendation aligns with the FDA-approved indication of blinatumomab for adult and pediatric patients with B-ALL.

The paradigm-changing results of AALL1731 and other recent clinical trials have revolutionized frontline therapy and established a new precedent, resulting in cure rates approaching 100% for all children with SR B-ALL and prompting therapy-reduction questions to be investigated in future trials. “Blin” for the win!