Blinatumomab Becomes Standard Addition to Consolidation Chemo in B-ALL, Irrespective of MRD Status

Since its initial approval in 2014, the role of blinatumomab (Blincyto) in the management of B-cell precursor acute lymphoblastic leukemia (B-ALL) has expanded significantly with evidence increasingly demonstrating its efficacy for both adult and pediatric patient populations, according to Daniel DeAngelo, MD, PhD, who added that the agent has become a standard addition to consolidation regimens regardless of minimal residual disease (MRD) status or backbone chemotherapy.

Most recently, in June 2024, blinatumomab was granted FDA approval for the treatment of adult and pediatric patients aged 1 month or older with CD19-positive, Philadelphia chromosome (Ph)–negative B-ALL in the consolidation phase, regardless of MRD status. The regulatory decision was supported by data from the phase 3 ECOG-ACRIN E1910 study (NCT02003222), which showed that patients with newly diagnosed, Ph-negative B-ALL in the blinatumomab arm (n = 112) achieved superior overall survival (OS) outcomes compared with those who received multiphase consolidation chemotherapy alone (n = 112). The 3-year OS rates were 84.8% (95% CI, 76.3%-90.4%) vs 69.0% (95% CI, 58.7%-77.2%), respectively, and the respective 5-year OS rates were 82.4% (95% CI, 73.7%-88.4%) vs 62.5% (95% CI, 52.0%-71.3%).

“Blinatumomab is a bispecific T-cell engager, and it's changed the way we think about the approach for our patients with ALL,” said DeAngelo, a professor of medicine at Harvard Medical School as well as chief of the Division of Leukemia and an institute physician at Dana-Farber Cancer Institute in Boston, Massachusetts. “We heard from the plenary talk at the 2024 ASH Annual Meeting that the addition of blinatumomab [to the consolidation phase] for pediatric patients improved their survival [outcomes]. [Accordingly,] most of us are going to try to incorporate blinatumomab into our pediatric-inspired regimens.”

In an interview with OncLive®, DeAngelo discussed up-front stratification and treatment considerations for patients with ALL; detailed considerations for transplant in unique phenotypes such as Ph-like and hypodiploid ALL; and highlighted how the most recent FDA approval of blinatumomab has expanded the agent’s use as a standard of care (SOC) beyond adult patient populations.

OncLive: How do you stratify and approach first-line treatment for patients with ALL, and what are the emerging strategies for incorporating biologic agents into treatment regimens?

DeAngelo: ALL is not a common disease. It's the most common cancer in pediatric [oncology], and [there] has been an incredibly successful history in terms of improving outcomes [for that population]. In adult patients, [efforts to improve] outcomes have been a little bit lackluster compared with our pediatric colleagues. In up-front cases, we typically stratify patients [according to whether they have] Ph-positive or -negative ALL. For Ph-positive [patients], the approach that most of us are taking is a second- or third-generation TKI plus minimal chemotherapy and adding blinatumomab to that approach.

For the Ph-negative patients, most of us will take an age-based approach [to treatment]. For patients in the adolescent and young adult [(AYA) population], we usually use pediatric-inspired regimens, and that includes asparaginase. [This is] a loosely defined group of patients. The National Cancer Institute and I would agree to define [AYA] as less than 40 years of age, [although] some places define it as less than 50 years, and some [others define it] as less than 30 years.

For our older patients, we're using lower-intensity therapies. That's where most of the effort and work will emerge. We also saw a lot of data from the 2024 ASH Annual Meeting incorporating some of our biologic agents, [namely] inotuzumab ozogamicin [Besponsa] and blinatumomab, with lower-intensity chemotherapy regimens. [Determining the] right regimen and the best way to incorporate [these agents into practice] is still a work in progress.

How do the distinctions between T-cell and B-cell ALL influence frontline treatment strategies?

When thinking about frontline therapy, [it is also important to bifurcate] whether patients have T-cell or B-cell disease; this is important because in older [patients], using fractionated inotuzumab ozogamicin plus low-dose chemotherapy, for example, is only going to be [effective] in CD22-positive or B-cell ALL. In younger patients, the addition of blinatumomab and other similar agents in the post-remission or consolidation setting, based on [data from] the phase 3 ECOG-ACRIN E1910 study [NCT02003222], is only going to be useful in B-cell ALL.

Many of the immunologic approaches have been abandoned in T-cell ALL. Some of us are adding nelarabine [(Arranon) injections], but most of us are incorporating age-based, pediatric-inspired [treatment] for young patients; for older patients, we are trying to advocate for a pure chemotherapy approach with or without the addition of nelarabine.

What considerations guide decisions about transplant in patients with unique phenotypes, such as Ph-like or hypodiploid ALL?

The big question here is, ‘What's the best TKI, and do patients who achieve minimal residual disease [MRD] negative status need to [undergo] transplant?’ We're transplanting fewer and fewer patients with [MRD negative status]. It's important to be cognizant of the fact that in the Ph-negative group, approximately one-third of patients are going to have something called a Ph-like [phenotype]. This is enriched in the Hispanic and Native American populations, and it portends a poorer prognosis. [Ph-like ALL is] often associated with an IKZF1 deletion, which is adversely prognostic [by itself]. Many of these patients will be candidates for transplant at first remission. Some of those patients may also have targetable lesions, such as a JAK2 mutation or another lesion that may be targeted by a TKI.

Other important frontline discussions [include] whether patients have hypodiploid [ALL]. For example, many [patients with low hypodiploidy will harbor] TP53 [mutations]. Some of them may have Li-Fraumeni syndrome. Others may be de novo cases, so they may not have a family history. That has important consequences in terms of taking those patients to transplant.

How has the role of blinatumomab evolved in B-ALL over the last decade?

Blinatumomab is useful because CD19 is ubiquitously expressed in virtually all cases of ALL. [Following] the agent’s initial [accelerated] approval [in relapsed/refractory B-precursor ALL], data from the [phase 3] TOWER study [(NCT02013167) confirmed] that in a randomized fashion in [patients with] relapsed/refractory disease, blinatumomab [produced] superior [OS outcomes] over standard chemotherapy. [Blinatumomab] became the standard approach for patients with relapsed disease.

Subsequently, the [confirmatory phase 2] BLAST study [NCT01207388] evaluated the use of blinatumomab for patients who were MRD-positive [after CR]. This [study comprised] 2 groups of patients: either those who were in remission but [did not] achieve MRD negativity, or those who—if they were to achieve MRD-negative remission—emerged with an MRD-positive clone. In those patients, the addition of blinatumomab followed by transplant improved [OS] outcomes, and a vast majority of patients were able to achieve MRD negativity. [This supported the agent’s FDA approval in] MRD-positive ALL.

Then [data from] the ECOG-ACRIN E1910 study [were presented in] a late breaking abstract [at the 2022 ASH Annual Meeting] and were published in the New England Journal of Medicine in the summer of 2024. This [study] used an adult regimen, so it [included patients] 30 [years of age] and older. They were using a backbone therapy based on the [phase 3] ECOG E2993 trial [NCT00002514], which hasn't been a popular regimen. Patients in remission [who were] MRD negative and Ph-negative were randomly assigned to receive continued chemotherapy, or they would receive [chemotherapy] plus 4 cycles of blinatumomab. There was a profound improvement in both event-free survival [EFS] and OS [with the addition of blinatumomab], which led [the FDA to extend the] label for [blinatumomab in 2024 to include] MRD-negative patients.

What have been the clinical implications of this FDA approval of blinatumomab in the consolidation phase for CD19-positive, Ph-negative B-cell precursor ALL?

The idea of incorporating blinatumomab as consolidation—regardless of MRD status—has now become a SOC. Based on the plenary talk at the 2024 ASH Annual Meeting showing that the addition of blinatumomab to a pediatric regimen in the consolidation phase improved EFS and OS, [blinatumomab’s use] now extends beyond the adult population, and it probably doesn't matter what the backbone chemotherapy is [used]. Virtually everybody's getting blinatumomab, whether they have relapsed/refractory disease, are MRD-positive, or have MRD-negative status. If a patient is Ph-positive, it's being incorporated with a TKI. Blinatumomab [is being more widely used] in trying to eradicate lymphoblast clones in the post-remission setting.

What are some other emerging areas of interest within ALL research?

[Another] exciting update [in ALL to emerge from] the 2024 ASH Annual Meeting is the whole field of menin inhibitors, [particularly for patients] with KMT2A rearrangements. These [alterations] are rare, [and are present in] approximately 5% to 8% of patients with ALL. These are difficult-to-treat [malignancies], and we often try to transplant patients. We now have a drug called revumenib (Revuforj) that was just FDA approved [in November 2024] for patients with relapsed/refractory KMT2A-rearranged acute leukemia. There will be ongoing trials [attempting to] incorporate [revumenib and] some of the new menin inhibitors into frontline therapy.

Reference

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 January 7, 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