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ALL Bispecific Abs and CAR T Strategies
Shifting the Paradigm in B-Cell ALL: Insights on the Evolving Role of Bispecific Antibodies and CAR T-Cell Strategies

Released: August 08, 2025

Ibrahim Aldoss
Ibrahim Aldoss, MD
Jae H. Park
Jae H. Park, MD
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Key Takeaways
  • Consolidation therapy with blinatumomab following induction therapy in newly diagnosed patients with B-cell ALL significantly improves overall survival.
  • Novel CD3 x CD19 bispecific antibodies, surovatamig and CN201, are designed to prolong half-life and reduce CRS.
  • Obe-cel CAR T-cell therapy appears to be associated with a lower incidence of severe CRS and ICANS than other approved CAR T-cell therapies.

This commentary summarizes key discussions and expert insights from a recent symposium on advances in bispecific antibody and CAR T-cell therapy for patients with acute lymphoblastic leukemia (ALL), featuring Ibrahim Aldoss, MD, and Jae H. Park, MD. In particular, this commentary captures their responses to important questions raised during the presentation related to the use of blinatumomab, the investigational bispecific antibodies surovatamig and CN201, and differences in the safety profiles of approved CAR T-cell therapies. These advancements promise to reshape the clinical management of ALL.

How are you using blinatumomab in the frontline setting?

Jae H. Park, MD:
The ECOG-ACRIN E1910 trial marked a practice-changing moment. This trial demonstrated the addition of blinatumomab in patients who were measurable residual disease (MRD) negative and in first complete remission can significantly improve survival. I usually incorporate blinatumomab into treatment earlier than in the original design of the ECOG-ACRIN E1910 trial. I administer blinatumomab after 2 cycles of chemotherapy, rather than after intensification—to preempt early relapse and improve tolerability. However, there is some debate regarding the optimal number of cycles, whether 2 or 4.

Ibrahim Aldoss, MD: 
I use blinatumomab with a CALGB 10403–based regimen and typically aim for 4 cycles. I also reduce maintenance therapy following blinatumomab. Counting 2 years of maintenance from the first blinatumomab dose helps streamline treatment length without compromising outcomes.

Are there patients with ALL who you would consider for blinatumomab retreatment at relapse after previous blinatumomab treatment?

Jae H. Park, MD:
Yes, but retreatment depends on relapse timing and CD19 expression on the leukemic blasts. The expression of CD19 should be rechecked after blinatumomab therapy because the antigen can resurface. CAR T-cell therapy can also be effective with low expression of CD19. If the relapse occurs after a significant treatment-free interval and CD19 expression is retained, reusing blinatumomab is reasonable. However, the expanding armamentarium now offers alternative agents with different mechanisms of action. This makes switching therapies—rather than repeating the same one—more appealing, especially when novel options might yield a better outcome.

What are the key differences between the emerging bispecific antibodies surovatamig and CN201 compared with blinatumomab?

Ibrahim Aldoss, MD:
The novel CD3 x CD19 bispecific antibody surovatamig (AZD0486) was engineered with a low-affinity CD3-binding site. This molecular change was designed to decrease cytokine release and the potential of cytokine release syndrome (CRS). Overall, preliminary results suggest that surovatamig is tolerable with 13% of patients in a small clinical trial experiencing adverse events that led to discontinuation, all of which were considered unrelated to surovatamig. Only 1 grade 3 CRS event and 1 grade 3 immune effector cell–associated neurotoxicity syndrome (ICANS) event occurred. Also, this bispecific antibody has a silenced Fc tail that prolongs the half-life, which is estimated to be between 8 and 12 days. In addition, preliminary evidence suggests that surovatamig is active in extramedullary disease, unlike blinatumomab.

CN201 is another novel CD3 x CD19 bispecific antibody. It has unique structural design changes that facilitate a prolonged drug half-life and modulation of the CD3 affinity, which reduces CRS potential. Although data are limited at this time, a phase I study suggested encouraging responses. Focusing on CRS, most of the events occurred early after the priming dose with 29.4% of patients experiencing any-grade CRS including 2 grade 3 events. No ICANS cases were reported with CN201 in this study.

In your practice, which patients do you recommend for the bispecific T-cell–engaging agents and which ones for CAR T-cell therapy?

Ibrahim Aldoss, MD:
The decision was easier when we only had intravenous blinatumomab. If the patient had extramedullary disease, I would choose CAR T-cell therapy over blinatumomab based on data indicating that CAR T-cell therapy is effective in this disease setting, in contrast to blinatumomab. It is very encouraging that we are seeing a response in extramedullary disease with surovatamig. Also, if a patient is not a candidate for an allogeneic stem cell transplant (SCT), I usually favor CAR T-cell therapy.

Jae H. Park, MD:
I have a similar approach. Currently, I consider the bispecific agents as a bridge to SCT until we obtain longer clinical follow-up data. I select CAR T-cell therapy for those patients who had a prior SCT and for whom I prefer not to give a second bone marrow transplant. Logistically, are there patients you think should not receive CAR T-cell therapy or for whom you would lean more toward bispecific agents?

Ibrahim Aldoss, MD:
Yes, I favor bispecific therapies for patients who have rapidly proliferating leukemia, where it is difficult to collect T-cells between cytoreduction cycles and then still allow time for the T-cells to recover. I also recommend bispecific T-cell–engaging antibodies for patients with high disease burden as a bridge to allogeneic SCT. Another group that I recommend for bispecific antibody therapy are patients who have low disease burden, especially when the treatment plan is to move to SCT quickly. Bispecific therapy is available off the shelf so that you can immediately move toward achieving an MRD-negative complete response. Then, if you have a donor, you can go to a SCT very quickly.

What are your thoughts about why the toxicity profile of obecabtagene autoleucel (obe-cel) differs from the other approved CAR T-cell therapies?

Jae H. Park, MD:
The obe-cel safety profile distinguishes it in comparison to the other 2 approved CAR T-cell therapies, tisagenlecleucel and brexucabtagene autoleucel (brexu-cel). The incidence of all-grade CRS toxicity with obe-cel was 69% in the FELIX trial, which is similar to the other approved CAR T-cell therapies, but the incidence of grade ≥3 CRS was 2%. In my experience, we typically see approximately 20% to 25% CRS toxicity with brexu-cel and approximately one half of those cases are grade ≥3. Similarly, obe-cell is associated with all-grade ICANS occurring in approximately one quarter of patients, with between 5% and 10% being grade ≥3 events. This rate of ICANS toxicity is lower than we have seen with the other CAR T-cell therapies in patients with ALL.

Although the reasons for this are not fully understood, there are 2 good hypotheses on what underlies the safety profile differences of obe-cel. The first is that the CD19-binding domain is different with a lower affinity, which may result in a dampening of the T-cell activation and consequently reduced inflammatory toxicity. The second hypothesis is that the split-dosing regimen used with obe-cel might allow for more controlled T-cell expansion, giving healthcare professionals a chance to intervene before severe cytokine release or neurotoxicity develops.

Your Thoughts
How are you using CAR T-cell therapies and bispecific antibodies for patients with ALL in your practice? What barriers have you encountered in using these therapies? Please join the discussion by answering the polling question or leaving a comment.

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