Adding Blinatumomab to Chemo Boosts Survival in Common Pediatric Leukemia, Results Show

Giving children with B-cell acute lymphoblastic leukemia (B-ALL) 2 nonsequential doses of blinatumomab (Blincyto; Amgen) between chemotherapy cycles improved disease-free survival (DFS) 61% in a phase 3 study by the Children’s Oncology Group (COG), who say this regimen represents the new standard for newly diagnosed patients.¹

The results reported this morning from the 66th American Society of Hematology (ASH) Meeting & Exposition in San Diego, California, have been anticipated, as blinatumomab’s dramatic benefits had prompted the COG data safety and monitoring committee to stop randomization early.

This is good news to patients and families of children diagnosed with B-ALL—despite an overall 5-year survival of 90%, some patients still relapse and there are disparities within that rate. One of the study’s bright spots is that Hispanic children, who have higher rates of B-ALL and worse outcomes, had proportionally greater benefit from blinatumomab.

Rachel Rau, MD | Image credit: Photo provided by ASH

B-ALL, which develops when the bone marrow produces an abundance of abnormal white blood cells, “is our most common cancer, and it's the ones that we care for most in the pediatric oncology arena,” lead study author Rachel Rau, MD, associate professor of pediatrics at Seattle Children’s, said in an interview with The American Journal of Managed Care^®.

Rau explained that the study population consisted of newly diagnosed patients with B-ALL who met National Cancer Institute (NCI) definitions of standard risk (SR), were younger than 10 years, and had a white blood cell count of 50,000, “which is about two-thirds of all pediatric B-ALL diagnoses.”

Patients were stratified by likelihood of relapse (average or high) and then randomized to receive either standard chemotherapy or 2 blinatumomab doses given between chemotherapy cycles. 

“The results of our randomization demonstrated that the addition of blinatumomab to that standard chemotherapy backbone significantly improved disease-free survival, because it was able to dramatically reduce the likelihood of a patient having a relapse,” Rau said. “So, the big picture implications are that most children with NCI standard risk be likely to benefit from the addition of blinatumomab to their upfront therapy.”

Results show the following:¹

• Patient accrual began June 28, 2019, with 1440 of 2245 eligible patients randomized by the cutoff date of June 30, 2024. Median age was 4.3 years; 52.6% were boys, 26% were Hispanic, and 5% were non-Hispanic Black.
• Median follow-up was 2.5 years. Following randomization, 722 patients were in the control arms and 718 in the blinatumomab arms.
• The 3-year DFS was 96.0% (SE ±1.2%) for the blinatumomab arms compared with 87.9% (2.1%) in the control arms, for an HR of 0.39 (95% CI, 0.24-0.64; 1-sided P < .0001).
• For SR average patients, the 3-year DFS was 97.5% (1.3%) for blinatumomab vs 90.2% (2.3%) for the control, for an HR of 0.33 (95% CI, 0.15-0.69); for SR high patients, 3-year DFS was 94.1% (2.5%) vs 84.8% (3.8%), for an HR of 0.45 (95% CI, 0.24-0.85).
• There were 6 deaths during remission; all among the SR high patients, none occurred during blinatumomab cycles.
• 56 relapses occurred among patients taking chemotherapy only, including 10 isolated central nervous system disease (iCNS) and 34 isolated bone marrow (iBM), and 5 combined. Of the 19 relapses among patients taking blinatumomab, 9 were iCNS, 9 iBM, and 1 combined.
• In the blinatumomab arm, 0.3% of first courses saw cytokine release syndrome and 0.7% saw seizures. This arm also saw a higher rates of sepsis and catheter-related infections, which Rau said might be due to the loss of B cells.

Investigators Make a “Leap”

The bispecific T-cell engager blinatumomab was the first therapy of its kind in 2014, when it received FDA approval as consolidation therapy for CD19-positive Philadelphia chromosome (Ph)–negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Although a decade old now, it was still a fairly new therapy when COG designed the study unveiled today, Rau said in the interview.

“Back in 2016 and 2017, we really just had early phase data in mostly relapsed, refractory patients. Most of that data were in adult patients, and so we had to make a little bit of a leap to say, ‘You know, there's enough data to say that it's going to be worth studying in a population of patients who in their baseline outcomes aren't terrible with chemotherapy alone.’ But the data that we had about blinatumomab was very convincing that it was at least safe.”

Rau noted that blinatumomab was very tolerable; although it had its own adverse effects, they were more manageable than the toxicity of chemotherapy and largely reversible.

“Then, the efficacy signal in those early days was already really promising. And so, we thought, if we were really going to make an impact on outcomes in a group that already is doing pretty well, this was our chance. This was an agent that looked like it could really move the needle,” she said.

The COG team turned out to be right. “But it was a bit of a leap, and it was the first Children's Oncology Group trial in NCI standard patients to use an investigational agent. This is a population that we kind of coddled because they already do pretty well, but we felt it was worth a little bit of a risk there to try this new and really very exciting drug, because it looked like it was quite safe and was very promising in terms of its early efficacy.”

Exciting News for a Group With Worse Outcomes

Blinatumomab offered benefits across most subgroups: both male and female patients, those with and without high-risk cytogenetic features, as well as varying degrees of benefit for White, Asian, and Black populations. But the benefit for Hispanic patients stands out: adding blinatumomab offered a 71% survival benefit over chemotherapy alone (HR, 0.29; 95% CI, 0.13-0.69). This is notable, given that Hispanic children develop B-ALL at rates 30% to 40% higher than White children, and Hispanic children with B-ALL also have a 40% higher death rate than other children with the disease.

Rau agreed the results are heartening for this population. “It’s super exciting,” she said. “I only recently moved to Seattle after having practiced in Houston, Texas, for almost 11 years. Our population in Texas was 65% Hispanic—so that one tug at my heart strings as well when I saw that substantial improvement. Hispanic patients historically have inferior outcomes compared to other races. We know that as a group, they have a genetic subtype called Ph-like disease. That may be one component [of the disparity], but there are probably other components.”

The Big Picture

“The big picture takeaways are that what we know right now is that blinatumomab, when added to a patient's chemotherapy, improves outcomes for a majority of patients with B-cell ALL,” Rau said. “What I would love see the field move towards—and I suspect will happen in the next set of trials—can we now replace some of those toxic chemotherapy elements?”

Second, Rau noted that while the study showed a drop in bone marrow–involving relapses, it did not produce similar results in the rarer cases in the central nervous system. “So, we still need to think about addressing that unmet need in the next set of trials,” she said.

Going forward, Rau noted the follow-up for this study is only 2.5 years, so patients will have to be followed to see how well they do for the long haul after receiving blinatumomab. She is encouraged by long-term data published in The New England Journal of Medicine earlier this this year.² “But we need to see that in our pediatric population as well.”

References

1. Rau R,Gupta S, Kairalla JA, et al. Acute B-cell lymphoblastic leukemia (B-ALL) is a type of blood cancer that occurs when the bone marrow produces too many abnormal B-lymphocytes, or immature white blood cells. Presented at: 66th American Society of Hematology Meeting & Exposition, December 7-10, 2024; San Diego, CA. Abstract 1.
2. Litzow MR, Sun Z, Mattison RJ, et al. Blinatumomab for MRD-negative acute lymphoblastic leukemia in adults. N Engl J Med. 2024;391(4):320-333. doi:10.1056/NEJMoa2312948