Emerging Data Continue to Shape the Role of Blinatumomab in Acute Lymphoblastic Leukemia

The evolving role of blinatumomab (Blincyto) in pediatric, adolescent and young adult (AYA), and adult acute lymphoblastic leukemia (ALL) has reshaped frontline and consolidation strategies, with data from the phase 3 ECOG-ACRIN E1910 trial (NCT02003222) and pediatric studies highlighting survival benefits generated by its use in select patient populations. However, unanswered questions regarding optimal patient selection, treatment sequencing, and the necessity of allogeneic stem cell transplant (alloHCT) underscore the need for further randomized data to guide its use in high-risk patient populations, according to Adam DuVall, MD, MPH.

After the initial FDA approval of blinatumomab in 2014, the agent had expanded to further indications in ALL. The latest regulatory update came in June 2024 when the FDA approved blinatumomab 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, irrespective of measurable residual disease (MRD) status.1 This approval was supported by data from ECOG-ACRIN E1910.

In an interview with OncLive®, Duvall highlighted data from several trials reported at the 2024 ASH Annual Meeting that further elucidated the role of blinatumomab in the ALL treatment paradigm. These included a study assessing outcomes with blinatumomab and alloHCT in the consolidation setting in newly diagnosed MRD-negative B-lineage ALL;2 the phase 3, randomized Children’s Oncology Group study AALL1731 (NCT03914625) evaluating blinatumomab plus chemotherapy in pediatric B-ALL;3 and an analysis of blinatumomab consolidation among older patients with newly diagnosed B-Lineage ALL from ECOG-ACRIN E1910.4

“[Adding blinatumomab to chemotherapy as consolidation] makes a huge impact [on outcomes],” DuVall said. “There is potentially an incredible benefit to using it, but we don't know the exact patient population that will truly benefit from it.”

DuVall is an assistant professor of medicine and pediatrics at the University of Chicago Medicine in Illinois.

OncLive: Since its initial FDA approval in 2014, how has the use of blinatumomab evolved, and what impact has this agent had on the ALL treatment paradigm?

DuVall: Adding blinatumomab to first-line therapy is commonly done now. However, a lot of [unanswered] questions remain, for better or worse, and the biggest concern that I have is that we're not going to get answers to some of those questions. [Patients] enrolled onto the E1910 study, [which evaluated] the addition of blinatumomab to [consolidation chemotherapy], were 30 to 70 years of age. However, there were very few [patients aged] 30 to 40 years, and there were very few over 55 years of age. If a [patient’s age is] between 40 and 55 years and they’re getting treated with the E1910 [regimen], they should be receiving blinatumomab in the frontline setting.

One question that remains is [whether] some people within that group might not benefit from blinatumomab. Looking at the older cohort in E1910, there didn't seem to be a benefit with adding blinatumomab [to consolidation chemotherapy]. [However, the trial] wasn't powered to detect that difference. Also, within the main age group, are there certain minimal residual disease [MRD]–negative patients who don't need blinatumomab? Looking at next-generation sequencing [NGS] data vs flow cytometry data reported thus far—and flow cytometry is sensitive down to 10-4 while NGS [has a sensitivity of] 10-6 —are there people more deeply MRD negative who wouldn't benefit from the addition of blinatumomab?

The other thing to point out is that most ALL treatment centers do not use the E1910 [regimen] as their backbone; therefore, we're extrapolating [the data] when [considering] adding blinatumomab to other [chemotherapy] backbones. I focus on treating adolescents and young adults [AYA], and we use pediatric-based approaches with more asparaginase and a lot more chemotherapy in general. Frequently, [blinatumomab] is being added [to these regimens] without any type of randomized data. That's where we're left because we don’t know if we'll end up ever getting randomized data comparing [the addition of] blinatumomab vs no blinatumomab in the AYA population. This also includes high-risk patients in pediatric populations. Some protocols are adding [blinatumomab] now in a nonrandomized fashion, but we don't know if that's the right thing, either.

[Adding blinatumomab] is not a small thing. This is adding 2 cycles, or an additional 12 weeks, [of treatment]. Especially for younger patients, who are going to be out of work, school, or other things, that 12 weeks alone can be quite disruptive, and if [blinatumomab] isn't needed, we shouldn't use it. Some people experience serious adverse effects [AEs] with blinatumomab. At the levels that we're using [blinatumomab], cytokine release syndrome [CRS] or any type of neurologic symptoms are very rare when patients have a low burden of disease. However, anecdotally, there are still a lot of patients who experience terrible fatigue, headaches, or other AEs that impact their quality of life significantly. When we're [considering] an additional 12 weeks [of treatment] but a patient might not need it, that’s when we should pause and have a little bit of humility by admitting that we don't have a clear answer [on whether this is more beneficial than other approaches.] Hopefully with some retrospective data or in some clinical trials through cooperative groups, we can get some answers to those questions.

Based on data from an abstract presented at the 2024 ASH Annual Meeting, what did findings show about the role of blinatumomab and alloHCT in the consolidation setting for patients with newly diagnosed, MRD-negative B-lineage ALL?

Patients who are MRD negative do not need an alloHCT transplant, and that need for alloHCT is not impacted by [the addition of] blinatumomab [to standard treatment]. Through work with the [prospective phase 2 CALGB 10403 trial (NCT00558519)] population, alloHCT worsened survival in general.

We have a good understanding that, in adult ALL, if we used an intensive approach, either with that E1910 regimen or the CALGB 10403 regimen, [the patient does] not need to receive transplant to consolidate. This is great because transplants are obviously incredibly toxic. We also have a lot of salvage medications now, so part of it might be that in the modern era, we can [successfully salvage more patients] with lots of targeted therapy. We still have inotuzumab ozogamicin [Besponsa]. We could theoretically re-treat patients with blinatumomab, or we could use CAR T cells or venetoclax [Venclexta]-based regimens. There are all sorts of other things that we can do.

In another presentation at the ASH Annual Meeting, what did data from Study AALL1731 show regarding the addition of blinatumomab to chemotherapy for newly diagnosed pediatric patients with B-ALL?

This is a game changer; it is practice changing. This trial answered a question for a specific population, and it's a clear answer. [The study evaluated patients with] standard-risk ALL, which [comprises] the vast majority of what pediatricians or pediatric oncologists still see. Those who had standard-risk–favorable disease either had favorable genetics, blood MRD negativity, and were MRD negative at the end of induction by flow [cytometry]; these patients were treated with standard-risk chemotherapy and didn’t receive blinatumomab.

However, they did randomly assign those patients who were standard-risk–average or –high. Standard-risk–high patients either have unfavorable or neutral genetics and have central nervous system [CNS] status, or they have an end of induction MRD that is greater than 0.01% by flow [cytometry]. Those unfavorable genetics are either an internal amplification of chromosome 21, an MLL rearrangement, hypodiploidy, or t(17;19). Favorable genetics [include] an ETV6/RUNX1 fusion or double trisomy at chromosomes 4 and 10. [Patients with these alterations] would be potentially standard-risk–favorable, depending on their MRD status at the end of induction.

Patients with standard-risk–average or –high disease were randomly assigned to either [chemotherapy alone or chemotherapy plus] blinatumomab at 2 different time points: after their standard consolidation or after interim maintenance. Those in the blinatumomab [arm] experienced improved overall survival. In the standard-risk–average and the standard-risk–high cohorts, even if you divided them, patients had improved disease-free survival [when treated in the blinatumomab arm]. That was predominantly [achieved] by reducing systemic relapses. [Blinatumomab plus chemotherapy] didn't actually reduce any isolated CNS relapses, but it did reduce systemic relapses. This makes sense because blinatumomab doesn't really penetrate the CNS. You still need to treat with CNS-directed therapy.

Notably, patients who were standard-risk–high and had an MRD greater than 0.1% were not eligible for randomization. They received blinatumomab either way.

Any standard-risk–high or –average patients should be getting blinatumomab. We actually don't have any data for standard-risk–favorable or high-risk patients, but at least [we know that] standard-risk–favorable patients shouldn't be getting blinatumomab right now.

For high-risk patients, a lot of people are adding [blinatumomab] in a nonrandomized fashion. They don't have any data for it, though.

What did the analysis from the ECOG-ACRIN E1910 trial detail about the use of blinatumomab as consolidation therapy in older patients with BCR::ABL1–negative B-lineage ALL?

Older ALL was defined differently in this analysis. They defined it as greater than 55 years, and this trial enrolled up to age 70. [The trial evaluated patients who] were MRD negative, because those who were MRD positive received blinatumomab in a nonrandomized fashion in this trial. Patients who were randomly assigned to the blinatumomab arm did not experience an OS or relapse-free survival benefit in this age group. However, it was a very small group, and outcomes were still good in this population. In the past, outcomes in older ALL were quite poor. OS [rates] were 71% for the blinatumomab group and 67% for the chemotherapy group at 3 years. These are great OS outcomes in this older patient population; there just wasn't a [statistically significant] difference between the 2 arms.

Looking at a subgroup analysis, it's hard to say that we shouldn't be using blinatumomab in this group. If we are using E1910 as our backbone, and we have a patient between the ages of 55 and 70, I would probably still use blinatumomab. A subgroup analysis shouldn't change one’s practice that much, and this one wasn't powered to show a difference. Because of those limitations, [the data] are interesting and suggest that although most of the time blinatumomab consolidation has won [over chemotherapy alone], that doesn't mean every population is going to benefit from its use. We should be a little bit more skeptical about it than I think we are currently.

Were there any other key data in ALL space presented at the ASH Annual Meeting?

[Practically] everything was about blinatumomab [at the 2024 ASH Annual Meeting]. The data from the phase 3 Alliance A041501 trial [NCT03150693] were presented with inotuzumab in the up-front setting…and [although] it seemed like [treatment with] inotuzumab resulted in more remissions, [a greater number of patients experienced] death during chemotherapy. It seemed like it worked, but it led to more toxicity, so obviously it's not ready for prime time in the up-front setting. In the future, we could potentially add it [to other regimens].

A couple of trials [contained] further data supporting the potential use of chemotherapy-free regimens in Ph-positive ALL. Ph-positive ALL, traditionally, was something that required transplant [and conferred] a much higher risk than Ph-negative ALL. However, with the discovery of TKIs and targeted therapy, outcomes [between Ph-positive and -negative patients] have become more similar. However, in the younger population, it's treated with very intense chemotherapy. This is not always tolerated by AYAs, let alone older adults.

It's been interesting to see the different [blinatumomab-based] combinations. One study was out of Europe, and one study was out of The University of Texas MD Anderson Cancer Center. The latter study evaluated the combination of blinotumomab with ponatinib [Iclusig]. These studies [evaluating blinatumomab] in slightly different ways with slightly different dosing, but it led to impressive OS without transplant.

We don't necessarily have a standard of care for Ph-positive ALL. There are different chemotherapy and TKI backbones and a lot of options out there. There are also different phase 2 studies, and the cooperative groups in the United States are performing some randomized studies to figure out the right treatment for Ph-positive ALL. It seems like less chemotherapy is probably the better option, certainly with some sort of TKI, such as dasatinib [Sprycel] and a step up to ponatinib or ponatinib to start with. Those [newer-]generation TKIs seem to be more powerful for our [patients with] Ph-positive ALL. [Hopefully these studies] will lead to more questions and studies in the future that give us a little bit more data regarding what we should be using.

Why is it important to optimize the use of blinatumomab and determine which patient populations can benefit the most from it?

We need phase 3 randomized data to figure out the right treatment, how many cycles, and when to give it. Do we need all this chemotherapy? Who do we give that to? For a lot of the highest-risk patients, whether they be high-risk pediatric patients or high-risk AYA patients, we don't have those data. We have the data for other patient populations, although some of them might be high risk.

Obviously, I'm incredibly biased. I almost only treat AYA patients with cancer or with ALL. It would be much more helpful to obtain these data [so I could] sit down with my patients in clinic and tell them, ‘Yes, we actually know what the right thing to do is.’ Right now, we don't have that information. I tell them the likely recommendations and [we talk about other] options, but there are no clear answers. That uncertainty causes a lot of psychosocial distress that I would love to avoid if we could have that data.

References

1. 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 February 6, 2025. 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
2. Liedtke M, Sun Z, Litzow MR, et al. Assessment of outcomes of allogeneic stem cell transplantation by treatment arm in newly diagnosed measurable residual disease negative patients with B-lineage acute lymphoblastic leukemia randomized to conventional chemotherapy +/- blinatumomab in the ECOG-ACRIN E1910 phase III National Clinical Trials Network trial. Blood. 2024;144(suppl 1):779. doi:10.1182/blood-2024-207557
3. Rau RE, Gupta S, Kairalla JA, et al. 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. Blood. 2024;144(suppl 1):1. doi:10.1182/blood-2024-207450
4. Podoltsev NA, Sun Z, Litzow MR, et al. Addition of blinatumomab to consolidation therapy among older newly diagnosed patients (pts) with BCR::ABL1 negative B-lineage acute lymphoblastic leukemia (ALL) in the ECOG-ACRIN E1910 randomized phase III trial. Blood. 2024;144(suppl 1):1. doi:10.1182/blood-2024-207450