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

Marlise R. Luskin, MD, MSCE

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 OncLive®.

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 P = .0003).¹

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, gained approval in November 2024 for the treatment of patients in this population.²

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.

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

Luskin: 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.³ 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].⁴ 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.

[Additionally], patients with KMT2A 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.

References

1. 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. Blood. 2022;140(suppl 2):LBA-1. doi:10.1182/blood-2022-171751
2. 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
3. Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847. doi:10.1056/NEJMoa1609783
4. Gökbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522-1531. doi:10.1182/blood-2017-08-798322