The treatment armamentarium for patients with relapsed/refractory acute lymphocytic leukemia (ALL) is rich with bispecific antibodies and CAR T-cell therapies that could shift to the frontline setting as studies continue; however, questions remain regarding the efficacy of sequential CD19-directed therapy, which future research will address, according to Marlise Luskin, MD, MSCE.

“The themes [for future research include developing] better [formulations of] blinatumomab [Blincyto], moving approved CAR T-cell therapies to the frontline setting, [developing] the next generation of CAR T-cell therapies, and [determining] CAR T-cell therapy bridging and post–CAR T-cell therapy approaches,” Luskin said in an interview with 

In the interview, Luskin discussed the strengths and limitations of the current treatment paradigm for patients with relapsed/refractory ALL; therapeutic advancements in the field, including blinatumomab and CAR T-cell therapy; and ongoing research seeking to integrate effective ALL agents into the frontline setting.

She discussed research with blinatumomab that solidified the agent’s role in the frontline setting, including data from the phase 3 ECOG ACRIN E1910 trial (NCT02003222), in which adult patients with B-cell ALL (B-ALL) in minimal residual disease (MRD)–negative complete remission had improved outcomes with frontline consolidation blinatumomab plus chemotherapy (n = 112) vs chemotherapy alone (n = 112); the median overall survival was not reached vs 71.4 months in these respective arms (HR, 0.42; 95% CI, 0.24-0.75; 2-sided 

She also described nuances in the role of CAR T-cell therapy for patients with ALL. Obecabtagene autoleucel (obe-cel; Aucatzyl), the most recent CAR T-cell product to receive FDA approval for adult patients with relapsed/refractory B-cell precursor ALL, 

 for the treatment of patients in this population.

Luskin is the educational director of the Adult Leukemia Program and a senior physician at Dana-Farber Cancer Institute, as well as an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts.

: What are the current challenges regarding the development of novel therapies within the relapsed/refractory ALL treatment paradigm?

: ALL is a unique disease and is different from some of the other diseases my colleagues and I manage. ALL, historically, has been a disease where we can get patients into remission most of the time—particularly younger patients, but patients of all ages. Most patients can get into remission with conventional chemotherapy, sometimes with relatively low-intensity chemotherapy or relatively minimal amounts of chemotherapy.

However, the challenge has been keeping patients in remission, making those remissions durable and getting patients cured. Historically, when a patient would relapse and we would have to go give chemotherapy again, that was rarely successful. [Salvage chemotherapy], particularly [after] relapse within the first year of or during frontline chemotherapy, was rarely effective, and the prognosis of relapsed/refractory ALL was dismal.

In the past couple years, we’ve started to move the needle. We now have multiple treatment options, particularly for patients with B-ALL, which has markers—CD19 and CD22—that allow us to use several novel agents that can be effective in getting patients back into remission. In those cases, we still have that problem of making those remissions stick, but we have had success in getting patients back in remission and having those durable second remissions, which is celebratory. However, one of the ongoing challenges is that we’re getting more patients to second remissions, and not all those remissions are durable. Trying to make more of those remissions durable is [an area] we’re working on.

What are the challenges associated with sequencing CD19-targeted agents in ALL? Is there potential for CD19 exhaustion when using different therapies directed at this target?

CD19 is probably the most important marker we’ve harnessed for ALL management, particularly for B-ALL. The first [CD19-directed] drug that has become used commonly is blinatumomab, a CD19/CD3-directed bispecific antibody that harnesses the immune system and brings the patients’ T cells—including B-ALL cells—to the CD19-positive cells to try to encourage endogenous T-cell–mediated killing of cancer cells. Blinatumomab was first developed for patients with relapsed ALL. Then, in the definitive phase 3 TOWER study [NCT02013167], blinatumomab was compared with and outperformed conventional chemotherapy [in patients with relapsed/refractory ALL].

Conventional chemotherapy is not effective in most patients [with relapsed ALL]. Blinatumomab was [more effective] but it still wasn’t as good as we would like. We went from getting approximately 10% or 20% of patients in [secondary] remission to getting 44% of patients back in remission.

 That’s an improvement to be celebrated, but it is not enough.

For most of those patients who got back into remission [with blinatumomab], the remissions were not durable. The durability of those remissions often was only several months, and then the patients would relapse, with the exception of patients who could convert that remission back to allogeneic transplant. There were some long-term survivors in that group but fewer than we would like.

Any time a drug gets an initial approval, research [is directed to] figuring out how we can use the drug better. Can we get more out of this drug by introducing it into treatment in a different way? Since that initial FDA approval for [blinatumomab for] relapsed disease, there were studies [assessing its effect on MRD levels] using flow cytometry to detect the presence of disease that was less than 5% but greater than 0.1%. [In the phase 2 BLAST trial (NCT01207388), treatment with blinatumomab led to secondary remissions in] 78% of patients [with MRD-negative B-cell precursor ALL].

 That’s a better remission rate than 44%.

What about bringing blinatumomab into the frontline setting? Why wait for patients’ disease to progress on therapy, or for them to have relapsed or recurrent disease of any amount? [Those questions have] prompted several trials incorporating [blinatumomab] into chemotherapy regimens in the frontline setting.

Now, we have multiple trials in patients of all ages showing that by integrating blinatumomab into frontline chemotherapy, we’re improving outcomes. Findings from the ECOG ACRIN 1910 study were presented [at the 2022] ASH Annual Meeting showing that adult patients who received chemotherapy plus blinatumomab did better than those who received chemotherapy alone. We had an exciting trial in infant ALL, which is a terrible diagnosis. That was not a randomized trial, but it compared [blinatumomab] with a prior chemotherapy, and there was a dramatic improvement [with blinatumomab].

[Then, the 2024 ASH Annual Meeting featured] one of those events you remember for your career: Seeing somebody up on the podium say we have moved the needle in childhood ALL. Fortunately, most children don’t get cancer, but every child who has cancer is a precious young person, and we want to cure as many of those patients as possible. We’ve cured most of them, but we hadn’t moved the needle in childhood ALL in approximately 20 to 25 years. There was a dramatic improvement in patients who had standard-risk ALL [who received blinatumomab plus chemotherapy vs chemotherapy alone], so now we have [advancements in the management of this disease] across the age spectrum.

The standard of care has brought blinatumomab to frontline therapy. Blinatumomab is effective. It works better when there’s low disease burden. The patients [with MRD-positive disease who receive this agent] are in remission, [so the agent manages an] amount of disease that we can’t detect—invisible reservoirs of disease below our limits of detection. It eradicates those [reservoirs] and prevents the relapse. [Blinatumomab] is now available to patients across the age spectrum, which is going to hopefully help us [deliver effective treatment] the first time for more patients. However, this will lead to additional challenges for patients who have relapsed after those therapies.

What is the role of CAR T-cell therapy in patients with relapsed ALL? How has this class of agents affected the later-line treatment paradigm?

Another exciting field is engineered T cells. Instead of trying to do matchmaking in the body, we’re removing a patient’s T cells and re-engineering them so they can target CD19-positive cells. This was another game changer in this field.

We now have 3 [CAR T-cell] products approved for B-ALL. We have tisagenlecleucel [Kymriah] for pediatric and young adult patients up to [the age of 25 years]. We have brexucabtagene autoleucel [brexu-cel; Tecartus] for adults [with relapsed/refractory B-cell precursor ALL]. Most recently, obe-cel [was FDA approved for this patient population]. Most adult patients are using the latter 2 products because of their age. Having multiple products is a great problem to have.

Over the next couple years, we’re going to figure out whether there are advantages to 1 product or another. [Brexu-cel and obe-cel] have somewhat different features and constructs, and [researchers have] theories about differences in performance, but they have not been compared head-to-head; cross-trial comparisons are challenging.

Obe-cel is exciting because the reports from the initial clinical trial—[the phase 1/2 FELIX trial (NCT04404660)]—were encouraging, [showing that the product] was safe. The rates of cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome were low, particularly those of grade 3 or higher. Those [findings] are remarkable because they were seemingly in significant contrast with brexu-cel. That makes [obe-cel] better for patients’ quality of life. That also means we can give [obe-cel] to more patients who we think can tolerate that product well.

The [CAR T-cell therapy] trials were done in patients who primarily had not received frontline immunotherapy. Most of those patients had not received blinatumomab in the frontline setting, although some had received it as salvage therapy, but we don’t yet have enough understanding of whether the efficacy of CD19-directed CAR T-cell therapy is going to be affected in patients who had received CD19-directed therapy in the frontline setting, or, in theory, in the salvage setting. The frontline question will be important for us to understand going forward.

There will hopefully be situations where there’s going to be a long interval of time between the 2 [lines of] therapy. Hopefully that means the [CAR T-cell] products will still be effective. There’s concern, primarily in the relapsed setting, that if a patient has progressed on blinatumomab, they may not respond as well [to subsequent CD19-directed therapy]. I’m hopeful that [CAR T-cell therapy is] still going to be a useful tool, but it deserves careful study going forward.

What ongoing ALL research might bring about the next big advance in the management of this disease?

With blinatumomab, [there is] a lot of interest in the development of subcutaneous administration. There’s an ongoing trial [that had] an update at [the 2024 ASH Annual Meeting]. That study is important.

Subcutaneous injection [involves] multiple-day injections. This is not trivial, but it means patients don’t have to be attached to a pump for a month at a time. That’s annoying for adults. It’s challenging for young patients and their parents. [The potential for subcutaneous injection] is exciting in terms of the convenience and potentially better efficacy because of the pharmacokinetics and drug exposure. That will be interesting to understand; it is being tested in the relapsed setting and will then be studied in the frontline setting.

With CAR T-cell therapy, there are 2 [notable] areas of research. The theme with blinatumomab, which works in the later-line settings, was: Can we move it forward? [Similarly], how do we bring CAR T-cell therapy forward? Should we, and how should we?

Right now, patients are generally [receiving CAR T-cell therapy at or after] second relapse. Can we move that [therapy] forward, even as far as frontline consolidation? That is not yet ready for prime time, but there’s a lot of interest in studying it.

Trials are now getting launched with an initial focus in the oldest patients, who don’t tolerate intensive chemotherapy and who may not desire or be anticipated to tolerate an allogeneic transplant. There’s a lot of interest in wondering whether we can induce patients with low-intensity [therapy] and then consolidate them with a CAR T-cell therapy, particularly obe-cel, which has a 4-1BB domain and may have durable persistence. Hopefully, there will be interest in further developing better CAR T-cell therapies.

[Patients’] mechanisms of relapse vary, but some of those relapses are due to CD19 loss or CD19-negative relapses. There’s interest in developing bispecific CAR T-cell therapies. Ongoing trials there will be interesting to watch.

There is also a lot of interest in understanding real-world data. What’s the best way to bridge [to CAR T-cell therapy]? Then, one of the biggest questions is: What do you follow CAR T-cell therapy with? Do you do a first transplant? If the patient has already received a transplant, do you do a second transplant? How do we get the most mileage out of that CAR T-cell therapy? How can we predict who needs additional therapy after the CAR T-cell therapy, whether it be a second transplant or more maintenance therapy?

How would you summarize the current state of the ALL treatment paradigm and where it is headed with ongoing research?

it’s always good to be an optimist. We are lucky now that we have multiple approved agents. We have blinatumomab, inotuzumab ozogamicin [Besponsa], and multiple CAR T-cell products. We now have treatment options for patients whose disease has come back. Improvements in the management of relapsed disease often inspires improvements in frontline therapy so that fewer patients need relapsed therapy. That’s a better scenario, but it means that patients who ultimately relapse after being exposed to one or more [agents—such as] blinatumomab and, in some patients, inotuzumab ozogamicin, in the frontline setting—often have a [challenging-to-treat form of the] disease. We are hopeful that those numbers [decrease], but patients who relapse need renewed attention for better treatment approaches.

[Additionally], a lot of the [research] has been done in relatively conventional B-ALL. [However], there are patient subgroups with high unmet needs, [such as] patients with T-cell ALL [T-ALL]. There are some early studies [investigating] CAR T-cell [therapies in this population], but there’s a dearth of treatment options for relapsed T-ALL.

 rearrangements, who often express CD19 but not CD22, are prone to lineage switches. Those patients don’t respond well to the lineage-targeted agents. We need to think of tailored, personalized therapies for those subgroups going forward.

Then, there is a [disease] entity called Philadelphia chromosome–positive ALL. All these themes apply to this subgroup as well, but [treatments need] to be integrated into a different paradigm along with a TKI. However, bringing blinatumomab forward is an area of research there [as well].

Patients who relapse after blinatumomab are a particularly high-risk group. Should we transplant them? How should we use CAR T-cell therapy? We have to consider different subgroups within a rare disease. However, there’s a lot of enthusiasm and great people working on this topic, and outcomes are going to continue to get better.

Litzow MR, Sun Z, Paietta E, et al. Consolidation therapy with blinatumomab improves overall survival in newly diagnosed adult patients with B-lineage acute lymphoblastic leukemia in measurable residual disease negative remission: results from the ECOG-ACRIN E1910 randomized phase III National Cooperative Clinical Trials Network trial. 

. 2022;140(suppl 2):LBA-1. doi:10.1182/blood-2022-171751

FDA approves obecabtagene autoleucel for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. November 8, 2024. Accessed November 8, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-obecabtagene-autoleucel-adults-relapsed-or-refractory-b-cell-precursor-acute

Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. 

. 2017;376(9):836-847. doi:10.1056/NEJMoa1609783

Gökbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. 

. 2018;131(14):1522-1531. doi:10.1182/blood-2017-08-798322

Articles

Marlise Luskin, MD, MSCE, discusses the treatment paradigm for relapsed/refractory ALL and research seeking to integrate agents into the frontline setting

Cellular Therapies and Novel Targeted Agents Will Shape the Future of R/R ALL Management

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.

 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 

 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.”

, 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.

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?

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 

 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 

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] 

 [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] 

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 

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 

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 

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 

-rearranged acute leukemia. There will be ongoing trials [attempting to] incorporate [revumenib and] some of the new menin inhibitors into frontline therapy.

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

Daniel DeAngelo, MD, PhD, discusses the expanded role of blinatumomab in B-cell precursor acute lymphoblastic leukemia management

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

Dr DeAngelo on the FDA Approval of Blinatumomab Consolidation in CD19+, Ph– B-ALL

“The idea of incorporating blinatumomab as consolidation regardless of MRD status has become a standard of care…this now extends beyond just the adult population, and it probably doesn’t matter what the backbone chemotherapy is.”

Daniel DeAngelo, MD, PhD, professor, medicine, Harvard Medical School; chief, Division of Leukemia, institute physician, Dana-Farber Cancer Institute, discusses the clinical implications of the FDA approval of blinatumomab (Blincyto) in the consolidation phase of multiphase chemotherapy for patients with CD19-positive, Philadelphia chromosome (Ph)–negative, B-cell precursor acute lymphoblastic leukemia (B-ALL).

 for the treatment of adult and pediatric patients aged 1 month or older with CD19-positive, Ph-negative, B-ALL in the consolidation phase, regardless of minimal residual disease (MRD) status. This approval expanded the use of blinatumomab as a standard of care in B-ALL management.

The regulatory decision was supported by data from the phase 3 ECOG-ACRIN E1910 study (NCT02003222), which evaluated the addition of blinatumomab to multiphase consolidation chemotherapy in patients with newly diagnosed, Ph-negative B-ALL. In this trial, patients in the blinatumomab arm (n = 112) achieved superior overall survival (OS) outcomes compared with those who received 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%). The hazard ratio for 5-year OS was 0.44 (95% CI, 0.25-0.76), confirming the benefit of incorporating blinatumomab into the consolidation regimen.

CD19, being ubiquitously expressed in B-ALL, has made blinatumomab a versatile therapeutic option for this population, DeAngelo says. The agent’s efficacy was first demonstrated in the phase 3 TOWER study (NCT02013167), which established blinatumomab as superior to standard chemotherapy in relapsed/refractory ALL, he notes. The approval of blinatumomab consolidation further underscores blinatumomab’s utility in both adult and pediatric populations, as blinatumomab is now a standard component of consolidation therapy, irrespective of patient MRD status, DeAngelo states.

Blinatumomab is now widely used in various clinical contexts, including as a consolidation therapy in MRD-positive and MRD-negative B-ALL, for relapsed/refractory disease, and in combination with TKIs for patients with Ph-positive B-ALL, the aim of which is to eradicate the lymphoblast clones in the post-remission setting, DeAngelo concludes.

Videos

Daniel DeAngelo, MD, PhD, discusses the FDA approval of blinatumomab in the consolidation phase in CD19-positive, Ph-negative B-cell precursor ALL.

Dr Jabbour on Frontline Treatment Considerations in ALL

"Every patient should have a full profile from the biology point of view. [If I have a patient who is] Philadelphia chromosome [Ph]–positive, they have a specific treatment. Then I move to [determine if patients in the] frontline [have] Ph-negative B-cell, T-cell, Burkitt lymphoma, or Ph-like ALL…and then all other patients."

Elias Jabbour, MD, professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses important frontline treatment considerations in newly diagnosed acute lymphocytic leukemia (ALL).

Treatment decisions for ALL are influenced by several critical factors, including patient age, immune phenotype, and disease biology, Jabbour begins. These factors guide initial therapy and help determine subsequent strategies such as transplantation or CAR T-cell therapy.

Patient age is a key consideration, as younger individuals generally tolerate intensive therapies better than older patients, Jabbour states. Older adults often have comorbidities and reduced tolerance to aggressive chemotherapy, necessitating tailored approaches to improve outcomes and minimize toxicity.

The immune phenotype, specifically whether the disease is B-cell or T-cell ALL, also dictates treatment strategies, he continues. Philadelphia chromosome (Ph)–positive ALL, for instance, requires TKIs such as imatinib (Gleevec) or dasatinib (Sprycel) combined with either chemotherapy or immunotherapy, Jabbour details. Conversely, patients with Ph-like or Ph-negative ALL follow distinct treatment pathways, emphasizing the need for comprehensive diagnostic profiling, he says.

Biological characteristics of the leukemia, such as hypodiploidy or other high-risk features, play a crucial role in planning post-remission therapy, Jabbour notes. For example, patients with hypodiploidy or other aggressive markers may benefit from frontline immunotherapy trials, yet they are likely candidates for subsequent transplantation to achieve durable remission, he explains. Similarly, patients with Burkitt's lymphoma or double-negative lineage ALL require unique therapeutic approaches, Jabbour adds.

Although up-front induction therapy may not always be heavily influenced by specific biological markers, these factors are critical for long-term treatment decisions, such as whether to pursue transplant as consolidation, Jabbour concludes.

Elias Jabbour, MD, discusses frontline treatment considerations in newly diagnosed acute lymphocytic leukemia.

 of obecabtagene autoleucel (obe-cel; Aucatzyl) has added another treatment options for patients with acute lymphoblastic leukemia (ALL) in the relapsed/refractory setting, contributing to the growing number of options for patients with this disease.

 In light of the growing number of treatments, molecular testing will be a key factor in determining which therapy is right for a given patient, according to Elias Jabbour, MD.

“We’re witnessing a revolution in ALL management, and it relies on a better understanding of ALL physiopathology [in order to] be able to discern different subsets molecularly and different [disease] entities, and as a result [determine] our therapy accordingly,” Jabbour, a professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with 

. “[It’s also] very important is to assess the depth of response [to frontline therapy] as early as possible and tailor the treatment according to the response. It’s time to personalize our therapy based on a molecular profile of a patient and a second [therapy] on a molecular response to treatment.”

In recent years, investigators have made great advancements in using gene expression data to molecularly and cytogenetically classify ALL subtypes.

 Established B-cell ALL entities include Philadelphia chromosome (Ph)–positive and –negative ALL, as well as ALL with 

 rearrangement, high hyperdiploidy, hypodiploidy, 

 rearrangement, and iAMP21. Novel entities added in recent years include B-cell ALL with 

High-risk cytogenetic characteristics in ALL include 

 rearrangements, complex cytogenetics, and low hypodiploidy or near haploidy.

 are also associated with a poor prognosis.

Blinatumomab Makes Its Mark in Frontline ALL

In the first line of therapy, the standard of care for adult patients with ALL is chemotherapy, often with hyper-cyclophosphamide-vincristine-doxorubicin-dexamethasone.

 Although optimized frontline chemotherapy approaches have displayed impressive results in pediatric patients, they have been less effective in older patients and are often accompanied by higher rates of toxicity.

“Older patients have a very poor tolerance to chemotherapy, [as well as those] with more aggressive disease biology; they need to be treated differently than younger patients,” Jabbour said.

However, partially due to the advances in molecular subtype classification in ALL, investigators have been able to develop the CD19- and CD3-directed T-cell engager blinatumomab (Blincyto) to augment traditional chemotherapy. 

, blinatumomab was approved by the FDA for the treatment of adult and pediatric patients aged 1 month or older with CD19-positive, Ph-negative B-cell precursor ALL in the consolidation phase.

 The regulatory decision was supported by findings from the phase 3 ECOG-ACRIN E1910 study (NCT02003222).

Findings from ECOG-ACRIN E1910 demonstrated that patients who received blinatumomab in addition to multiphase consolidation chemotherapy (n = 112) achieved a 3-year overall survival (OS) rate of 84.8% (95% CI, 76.3%-90.4%) compared with 69% (95% CI, 58.7%-77.2%) among patients who received consolidation chemotherapy alone (n = 112; HR, 0.42; 95% CI, 0.24-0.75; 

 At a median follow-up of 4.5 years, the 5-year OS rates were 82.4% (95% CI, 73.7%-88.4%) and 62.5% (95% CI, 52.0%-71.3%), respectively (HR, 0.44; 95% CI, 0.23-0.76).

The efficacy of blinatumomab monotherapy was evaluated vs IntReALLHR2010 HC3 intensive combination chemotherapy as the third consolidation cycle in the phase 3 Study 20120215 (NCT02393859). Patients who received blinatumomab (n = 54) achieved a 5-year OS rate of 78.4% (95% CI, 64.2%-87.4%) vs 41.4% (95% CI, 26.3%-55.9%) among patients who received chemotherapy (n = 57; HR, 0.35; 95% CI, 0.17-0.70). The 5-year relapse-free survival rates were 61.1% (95% CI, 46.3%-72.9%) and 27.6% (95% CI, 16.2%-40.3%), respectively (HR, 0.38; 95% CI, 0.22-0.66). ˙

In the safety population of ECOG-ACRIN E1910, the most common any-grade adverse effects (AEs) that occurred in the blinatumomab arm (n = 111) included neutropenia (82%) thrombocytopenia (75%), anemia (59%), leukopenia (43%), and lymphopenia (32%). These events occurred in the chemotherapy arm at respective rates of 89%, 75%, 50%, 57%, and 25%. Fatal AEs were reported in 2 patients in the blinatumomab arm; patients in this arm also experienced dose interruptions (5%) and reductions (28%), and 2% were forced to discontinue treatment due to AEs.

Recent FDA Approvals Add Options in Relapsed/Refractory ALL

The most recent FDA approval in the relapsed/refractory ALL space was the CD19-directed genetically modified autologous T-cell immunotherapy obe-cel.

 The agent earned an indication for the treatment of adult patients with relapsed or refractory B-cell precursor ALL. The regulatory decision was supported by findings from the phase 1/2 FELIX trial (NCT04404660).

“[Although] the approval is for [relapsed]/refractory ALL, [obe-cel] will [eventually] be used earlier in the disease stage of ALL, [including] in [minimal residual disease] MRD–negative patients and frontline patients,” Jabbour noted.

Data from FELIX demonstrated that efficacy-evaluable patients (n = 65) achieved a complete remission (CR) rate within 3 months of 42% (95% CI, 29%-54%).

 Notably, the median duration of CR among these responders was 14.1 months (95% CI, 6.1-not reached [NR]). The overall CR rate was 63% (95% CI, 50%-75%) with a median duration of CR of 14.1 months (95% CI, 6.2-NR).

Obe-cel is unique among cellular therapies in that it is administered via split dosing, allowing for a higher dose (100 × 10

 CAR T cells) to be given on day 1 in patients with a low tumor burden (bone marrow blasts ≤ 20%) or at a lower dose (10 × 10

 CAR T cells) in patients with a high tumor burden (bone marrow blasts > 20%). Patients with a low tumor burden receive 310 x 10

 CAR T cells on day 10 if they did not experience grade 3 or higher cytokine release syndrome (CRS) or any-grade immune effector cell–associated neurotoxicity syndrome (ICANS); patients with high tumor burden receive 400 x 10

 CAR T cells on day 10 if they did not experience grade 3 or higher CRS or any-grade ICANS. In terms of safety, any-grade CRS occurred at a rate of 75% and at a rate of 3% for grade 3 events. Any-grade ICANS was reported in 24% of patients and 7% of patients had grade 3 or greater ICANS.

“This [dosing] strategy is safe and effective, but the [CAR T] cells are persistent,” Jabbour explained. “The advantage [of obe-cel] is that it is safe, effective, and leads to a persistent response and a plateau that will make this a viable option to be a finite therapy, where patients will have durable control of the disease with no concerns whatsoever. [These characteristics] will allow obe-cel to move to the frontline, or early on, in the treatment strategy compared with other CAR [T-cell agents].”

Beyond obe-cel, there are 2 other cellular therapies approved by the FDA for the treatment of patients with relapsed/refractory ALL: the CAR T-cell agents tisagenlecleucel (tisa-cel; Kymriah) and brexucabtagene autoleucel (brexu-cel; Tecartus).

 Tisa-cel was approved in August 2017 for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.

 In October 2021, brexu-cel earned FDA approval in adult patients with relapsed/refractory B-cell precursor ALL.

The FDA approval of tisa-cel was supported by findings from the phase 2 ELIANA trial (NCT02435849), which demonstrated that patients who received tisa-cel (n = 63) achieved a CR/CR with incomplete count recovery (CR/CRi) rate of 83% (95% CI, 71%-91%); the median duration of remission was NR (95% CI, 7.5-not evaluable).

 Additionally, 83% of patients (95% CI, 71%-91%) achieved a CR/CRi with MRD-negative bone marrow. Tisa-cel was the first CAR T-cell agent to earn FDA approval.

Data from the phase 1/2 ZUMA-3 study (NCT02614066) supported the approval of brexu-cel and showed that efficacy-evaluable patients (n = 54) achieved a CR/CRi rate of 64.8% (95% CI, 51%-77%), including a CR rate of 51.9% (95% CI, 37.8%-65.7%).

 The median duration of remission was 13.6 months (95% CI, 9.4-NE) and the median duration of remission among patients who experienced a CR was NR (95% CI, 9.6-NE). 

Outside of cellular therapies, the FDA has also recently approved the CD22-directed antibody-drug conjugate inotuzumab ozogamicin (Besponsa) for the treatment of pediatric patients at least 1 year of age with relapsed/refractory CD22-postive B-cell precursor ALL.

 was supported by findings from the phase 2 Study WI203581 (ITCC-059; NCT02981628).

Data from Study WI203581 demonstrated that the CR rate among all patients who received inotuzumab ozogamicin (n = 53) was 42% (95% CI, 28.1%-55.9%), with a median duration of CR of 8.2 months (95% CI, 2.6-NE).

 Most patients (95.5% [95% CI, 77.2%-99.9%]) achieved MRD negativity via flow cytometry and 86.4% (95% CI, 65.1%-97.1%) experienced MRD negativity by RQ-PCR.

In terms of safety, 21% of patients discontinued treatment with inotuzumab ozogamicin and 11% experienced dose interruptions. Any-grade AEs included pyrexia (49%), anemia (45%), and vomiting (45%). Grade 3 or higher AEs included anemia (38%), febrile neutropenia (28%), and infection (23%).

NCCN ALL Guidelines Continue to Evolve in 2024

Over the course of 2024 there were several notable updates to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for ALL.

 Notable updates in version 1.2024 of the guidelines from version 4.2023 included modifying T-cell ALL to include adding T-cell ALL, not otherwise specified, cortical type, mature type, and early T-cell precursor ALL. The guideline panel also noted that early T-cell precursor ALL usually lacks expression of CD5, CD8, and CD1a, as well as expression of at least 1 myeloid/stem cell marker.

In terms of treatment updates to the guidelines, blinatumomab in combination with a TKI was added as a new therapy option for adolescent and young adult patients, as well as patients who are less than 65 years old without substantial comorbidities, during the induction phase. This combination was also added as a new therapy option for adult patients who are at least 65 years old or with substantial comorbidities.

In the consolidation phase, patients with persistent or rising MRD gained inotuzumab ozogamicin with or without a TKI as a new therapy option. Additionally, the top treatment pathway was modified to consider allogeneic hematopoietic cell transplantation for these patients. Blinatumomab plus a TKI was noted as the preferred regimen in consolidation regardless of MRD status for the treatment of patients who are blinatumomab naive.

“We’re making significant progress towards curing ALL in adult patients, [in addition to] pediatric [patients]; it is going to happen in our lifetime,” Jabbour said in conclusion.

FDA approves obecabtagene autoleucel for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. November 8, 2024. Accessed December 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-obecabtagene-autoleucel-adults-relapsed-or-refractory-b-cell-precursor-acute

Davis K, Sheikh T, Aggarwal N. Emerging molecular subtypes and therapies in acute lymphoblastic leukemia. 

. 2023;40(3):202-215. doi:10.1053/j.semdp.2023.04.003

Jabbour E, Short NJ, Jain N, et al. The evolution of acute lymphoblastic leukemia research and therapy at MD Anderson over four decades. 

. 2023;16(1):22. doi:10.1186/s13045-023-01409-5

Aldoss I, Roboz GJ, Bassan R, et al. Frontline treatment of adults with newly diagnosed B-cell acute lymphoblastic leukaemia. 

. 2024;11(12):E959-E970. doi:10.1016/S2352-3026(24)00285-0

FDA approves blinatumomab as consolidation for CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia. FDA. June 14, 2024. Accessed December 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-blinatumomab-consolidation-cd19-positive-philadelphia-chromosome-negative-b-cell

Blincyto. Prescribing information. Amgen; 2024. Accessed December 4, 2024. https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Blincyto/blincyto_pi_hcp_english.pdf

Aucatzyl. Prescribing information. Autolus, Inc; 2024. Accessed December 4, 2024. https://www.fda.gov/media/183463/download?attachment

FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. FDA. Updated September 7, 2017. Accessed December 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-b-cell-all-and-tocilizumab-cytokine-release-syndrome

FDA approves brexucabtagene autoleucel for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. October 1, 2021. Accessed December 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-b-cell-precursor-acute-lymphoblastic

Kymriah. Prescribing information. Novartis; 2017. Accessed December 4, 2024. https://www.fda.gov/media/107296/download

Tecartus. Prescribing information. Kite Pharma Inc; 2020. Accessed December 4, 2024. https://www.fda.gov/media/140409/download

FDA approves inotuzumab ozogamicin for pediatric patients with acute lymphoblastic leukemia. FDA. March 6, 2024. Accessed December 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-inotuzumab-ozogamicin-pediatric-patients-acute-lymphoblastic-leukemia

Besponsa. Prescribing information. Pfizer, Inc; 2024. Accessed December 4, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761040s003lbl.pdf

NCCN. Clinical Practice Guidelines in Oncology. Acute lymphoblastic leukemia, version 2.2024. Accessed December 4, 2024. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf

Recent advancements in the treatment of acute lymphoblastic leukemia (ALL) have been marked by the approval of several novel therapies, including CAR T-cell therapies and monoclonal antibodies. These therapies target specific molecular subtypes, offering personalized treatment options for patients with relapsed or refractory B-cell precursor ALL. The FDA has approved drugs like obecabtagene autoleucel, blinatumomab, and inotuzumab ozogamicin, reflecting a shift towards targeted therapies. These developments underscore the importance of molecular profiling in guiding treatment decisions and improving patient outcomes in ALL.

The therapeutic arsenal for patients with ALL in the first line and beyond is expanding beyond traditional approaches, enabling better outcomes for patients.

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