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Young adults with B-cell acute lymphoblastic leukemia (ALL) with high-disease burden are a high-risk population who may benefit from further interventions to improve outcomes after chimeric antigen receptor (CAR) T-cell therapy, according to a real-world study.

In an attempt to understand the variables affecting outcomes, Liora Schultz, MD, of Stanford University in California, and colleagues created a national consortium to enable cross-institutional reporting and analysis. In addition to overall outcomes, the team reported response, toxicity, and survival data, as stratified by disease burden. The results, published in the , showed that patients with a high-disease burden had inferior outcomes, with 12-month rates of overall survival (OS) of 58% and event-free survival (EFS) of 31% compared with patients categorized as having a low-disease burden (OS 85%, EFS 70%) or with undetectable disease (OS 95%, EFS 72%).

In the following interview, Theodore W. Laetsch, MD, who leads both the Developmental Therapeutics Program and the Very Rare Malignant Tumors Program at the Children's Hospital of Philadelphia, discussed the details of the team's study, which is the first analysis of commercial tisagenlecleucel stratified by disease burden.

What does the study add to the literature?

Laetsch: Multiple studies, including ours, have now shown that children and young adults treated in the real-world setting have on average a lower disease burden than those patients treated on the clinical trials that led to approval of tisagenlecleucel. We knew that patients with lower disease burden have less toxicity with CAR T-cell therapy, but the impact of disease burden on efficacy wasn't clear. While lower disease burden could obviously be good, there was some concern that there may not be enough leukemia to cause the CAR T-cells to grow and persist to control the disease in the long-term.

In this study, we found that outcomes are better for children with lower disease burden compared with those with higher disease burden. Specifically, the chance of the patient's leukemia relapsing after treatment is less in patients with lower disease burden and the OS is better for those with low or no detectable disease compared with those with high-disease burden. We also confirmed what was already known, that the chance of severe cytokine release syndrome was much lower in those with low-disease burden.

Were there any surprises in the data?

Laetsch: The biggest surprise in the data was the impact of disease burden on outcome. We didn't originally start this research to study that question specifically. We were looking to report the outcomes of patients treated with commercial tisagenlecleucel in the real-world setting shortly after FDA approval. Our initial goal was to see how these outcomes compared with those from the trial that led to approval. The impact of disease burden was striking in the initial analysis of our data and led us down this path.

How could high-disease burden patients be converted to low-disease burden patients?

Laetsch: We don't yet know whether it is truly the disease burden that impacts outcome, or whether the disease burden is just a reflection of underlying biologic differences in patients' leukemias. It could be that patients with the most treatment-refractory leukemia have higher disease burden because their leukemia doesn't respond as well to chemotherapy before CAR T-cell therapy. These same biologic factors could make the leukemia less responsive to CAR T-cell therapy. In this case, even if we could reduce the disease burden, it may not impact the patient's outcome.

Alternatively, outcomes may truly be driven by disease burden and patients could be given more intense therapy prior to CAR T-cell therapy to reduce their disease burden. The downside of giving more intense therapy is that there is a greater chance of side effects, some of which can be serious or life-threatening. Severe side effects could prevent the patient from being able to receive CAR T-cell therapy. Further studies are needed to evaluate whether more therapy to reduce disease burden prior to CAR T-cell therapy will improve outcomes.

Are further studies planned in this area?

Laetsch: This study was retrospective and gathered real-world data from a large number of hospitals. While that is a strength, it is also a limitation as not all hospitals/physicians evaluated disease burden at the same time points and in exactly the same way. As noted, studies are needed to see whether additional therapy prior to CAR T-cell therapy can reduce the disease burden and improve outcomes. In addition, it will be important to continue to evaluate the role of stem cell transplant after CAR T-cell therapy, especially for patients with high-disease burden.

What is the basic message for practicing oncologist?

Laetsch: I would encourage oncologists to consider CAR T-cell therapy early in the disease course for patients with relapsed and refractory ALL. Hopefully, we can achieve better outcomes for our patients by treating before their leukemia becomes so unresponsive that it can't be controlled.

Read the study here and expert commentary about it here.