Blinatumomab Consolidation Prevents B-ALL Relapses and CAR T-Cell Therapy Consolidation May, Too

Gregory Roloff, MD

FDA-approved therapies in the relapsed B-cell precursor acute lymphoblastic leukemia (B-ALL) setting are under examination as consolidation approaches, with blinatumomab (Blincyto) and CAR T-cell therapy showing notable efficacy as consolidation therapies, according to Gregory Roloff, MD.

Overall survival (OS) was significantly improved when blinatumomab was added to consolidation chemotherapy in adult patients with minimal residual disease (MRD)–negative B-ALL remission who were treated in the phase 3 E1910 study (NCT02003222).1 At a median follow-up of 43 months, 3-year OS rates were 85% in the blinatumomab plus chemotherapy arm (n = 112) vs 68% in the chemotherapy alone arm (n =112; HR, 0.41; 95% CI, 0.23-0.73; P = .002). Additionally, the 3-year relapse-free survival rates were 80% and 64%, respectively (HR, 0.53; 95% CI, 0.32-0.87). The agent received approval from the FDA for use in adult and pediatric patients aged 1 month and older with CD19-positive Philadelphia chromosome–negative B-ALL in the consolidation phase of multiphase chemotherapy.2

Regarding CAR T-cell therapy in this patient population, a phase 1 pilot study (NCT05707273) from City of Hope showed that at a median follow-up of 175 days (range, 44-433) their memory-enriched CAR T-cell product led to a MRD-negative complete remission in 10 of the 11 patients who completed the dose-limiting toxicity (DLT) period.3 The patient who experienced molecular relapse received an allogeneic hematopoietic cell transplantation and is in complete remission.

“It became an interesting question to ask: If we were to give CAR T-cell therapy not in a state of relapse, but in a state of remission and even a residual disease–negative remission, might patients tolerate it and do well with it from a toxicity standpoint? Perhaps, with longer-term follow-up, might we see fewer relapses?” Roloff asked in an interview with OncLive®.

In the interview, Roloff detailed data on consolidation therapy with blinatumomab or CAR T-cell therapy for B-ALL, and the role of these agents in this setting. Roloff is an assistant professor of medicine and hematologist at UChicago Medicine in Illinois.

OncLive: What role does blinatumomab have in the consolidation setting?

Roloff: A recently published, practice-changing paper in the New England Journal of Medicine by Mark R. Litzow, MD, was on the E1910 trial. It was a large cooperative group study that incorporated [blinatumomab], which is currently FDA approved for patients who have relapsed B-ALL, into upfront therapy. This study was initially designed to test whether blinatumomab could be added to the consolidation portion of therapy for patients with ALL and not [be] used once they reached the relapsed setting. [The idea is that it would] deepen responses along the way and potentially prevent fewer relapses. Blinatumomab [is now] approved as an FDA-available therapy for patients who have residual disease [and CD19-positive Philadelphia chromosome–negative B-ALL in the consolidation phase].

Naysayers might say: If there’s no detectable residual disease, what are you treating? One of the things that we’ve come to learn is that there can be tiny bits of detectable disease, even under the limits of what our assays can sensibly detect right now. The question became, even in patients who have a negative residual disease status, might blinatumomab lead to better outcomes for them as well?

The results of ECOG [E1910], which have been presented a couple of times at the ASH Annual Meeting leading up to the publication of this paper in the New England Journal of Medicine, looked very promising along the way. The trial ended up being stopped early because at an interim analysis the difference [in disease-free survival] was so striking regarding the patients who received blinatumomab vs those who did not. Since the publication of this trial, this [regimen] has begun to be incorporated into standard consolidation therapies for patients, even when they don’t have any detectable residual disease, which was the initial indication for blinatumomab [in its] development. We think and hope now that this drug is being incorporated into routine therapies that we may see fewer relapses because those bits of disease that we were failing to detect initially along the way may be addressed.

One of the interesting observations that I believe we need to make as a field from a real-world type of study is: What does the new incidence of ALL become if you’re using a standard blinatumomab consolidative approach? Only time will tell. I expect longer-term follow-up from the study [will] eventually be published, but I would also be curious to see what the experience is on the ground for investigators who choose to incorporate this drug into their standard practice.

Are there questions regarding blinatumomab’s efficacy in this setting based on patient age?

This was one peculiarity that was part of that same story that I don’t think we quite understand yet. We saw an advantage to the addition of blinatumomab for consolidative therapy in the E1910 trial. But if you split out [the data] into subgroups and try to see if there are certain patient populations or certain attributes of patients that drive that signal, it seemed that [most] of the signal for better outcomes with blinatumomab [vs the chemotherapy alone arm] was driven by younger patients below 55 years of age. If you were to do a stratified [age] analysis—55 and below or 55 and above—the 55 and above [group experienced less of a benefit]. For whatever reason, [most of] that survival signal was carried along by the 55 and below [group]. We don’t quite understand why that is because as part of this multivariable analysis they looked at other known negative prognostic markers such as disease biology. That’s going to be one of the lingering questions that longer-term follow-up or perhaps some real-world studies may be positioned to address.

How could CAR T-cell therapy sequencing shift in B-ALL with trials examining the consolidation setting?

A provocative abstract that was interesting questioned the position of where CAR T-cell therapy falls within our therapeutic sequence. Right now, all the CAR T-cell therapies that we have are designed for patients who were in remission and then subsequently experienced a relapse or the first signs of relapse.

Just like the idea of adding blinatumomab closer to the frontline [setting], Ibrahim T. Aldoss, MD, and his team at City of Hope presented on this relatively small, but interesting and important trial that they are in the process of completing at City of Hope where they gave a CAR T infusion to patients who were in a first complete remission. This was a homegrown, CAR T-cell therapy that they developed in their laboratories, but [it was] similar in design to the ones that we have available.

They were, like the blinatumomab [trial] I detailed, giving it to patients who were negative for any residual disease that we could detect and in remission. This is in the spirit of relapse prevention because we know that a pretty sizable proportion of patients who have these residual disease-negative detection remissions will still go on to relapse. The idea is that there are low-level bits of disease hanging out somewhere that our tests are simply not finding. We know from published studies that CAR T-cell therapies work well when we’re talking about relatively small amounts of disease that they can go and mop up and scavenge.

What would be an advantage of giving CAR T-cell therapy in a state of remission?

The potential advantages for this type of approach are multifold. The first is that, if you’re giving a CAR T-cell therapy [to a patient] in a first complete remission, it means the patient has not yet had multiple lines of therapy that have led to several relapses. From the standpoint of patient fitness, cumulative morbidity, [and] cumulative treatment toxicity, they may be in a bit of a better place if you’re giving this [therapy] earlier on as opposed to when they’ve had 4 or 5 relapses, tons of chemotherapy, prior stem cell transplants, and some of the morbidity that [is tough on] patients along the way in that process.

Also, we give patients an infusion of their own T cells back and although the translational science of what ALL therapies do to the fitness of T cells and how that may lead to different outcomes for a CAR T-cell product is not well flushed out yet, it’s sensible to hypothesize that if we’re making CAR T-cell products [out] of a patient’s T-cell compartment that has not seen multiple lines of cytotoxic therapy those cells may be more robust and lead to a better CAR T-cell product. But that’s still a hypothesis; it’s not been well validated.

The final thing is it could be potentially convenient for patients to get a therapy that is going to deepen their remission and, from a logistical standpoint, prevent them from [receiving] 2 or 3 years of maintenance therapy [that entails] coming back and forth and getting lots of chemotherapy for relapse prevention. This may be more of a “one and done” type of approach to prevent relapses. For those 3 reasons, I thought the approach to this [City of Hope] trial was interesting and worth exploring.

What data were seen when CAR T-cell therapy was given in a consolidation setting in the City of Hope study?

The trial is ongoing. It’s a single-center study and Dr Aldoss presented [data] on patients who have received it so far. The median follow-up time to date is relatively short, but [the CAR T-cell therapy] was incredibly well tolerated, and they did not see any significant high-grade toxicities from the T-cell infusion itself. Most of those patients who [completed the DLT period and] were in remission from the get-go have held on to their remission. There was 1 patient who started to convert to a state of MRD positivity, and that patient ended up being salvaged with a transplant. But after CAR T-cell therapy, the rest of the patients have remained in remission without additional maintenance therapies to keep them there and tolerated this therapy well with minimal adverse effects. It’s interesting from that regard because this may be an opportunity for a larger study to examine the actual incidence of relapse prevention if we are using immunotherapies in the consolidative setting vs relapsed setting.

References

1. 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
2. FDA approves blinatumomab as consolidation for CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia. FDA. June 14, 2024. Accessed March 25, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-blinatumomab-consolidation-cd19-positive-philadelphia-chromosome-negative-b-cell
3. Aldoss I, Wang X, Zhang J, et al. CD19-CAR T cells as definitive consolidation for older adults with B-cell acute lymphoblastic leukemia in first complete remission: a pilot study. Blood. 2024;144(suppl 1):966. doi:10.1182/blood-2024-201784