From December 7 to 10, 2024, the 66th American Society of Hematology (ASH) Annual Meeting was grandly held in San Diego, USA. Hematology experts and scholars from around the world gathered to discuss and exchange insights on the latest research advancements in the field.

At this year’s conference, Dr. Sumit Gupta from The Hospital for Sick Children in Toronto, Canada, and his team presented the latest findings from the AALL1731 study (Abstract #1). This study explored the efficacy and safety of adding blinatumomab to standard chemotherapy in pediatric patients with standard-risk acute B-lymphoblastic leukemia (B-ALL).To delve deeper into the study, Hematology Frontier conducted an exclusive interview with Dr. Sumit Gupta, who shared the key findings of the AALL1731 study. The interview is summarized below.

Hematology Frontier: Could you summarize the main findings of the AALL1731 study?

Dr. Sumit Gupta: AALL1731 is a randomized clinical trial conducted by the Children’s Oncology Group (COG), co-led by Dr. Rachel Rau and myself. This study enrolled pediatric patients with standard-risk acute B-lymphoblastic leukemia (B-ALL) who had an intermediate or higher risk of relapse. These patients were categorized into the standard-risk average (SR-A) and standard-risk high (SR-H) groups. They were randomly assigned to receive either standard chemotherapy or standard chemotherapy combined with two cycles of blinatumomab.

Blinatumomab is an immunotherapy agent that targets CD19 on B cells and recruits the patient’s own T cells to attack and eliminate leukemia cells. During the first interim analysis, the Data Safety Monitoring Committee halted the study due to the overwhelmingly positive results of blinatumomab.

For instance, in the SR-A group, the three-year disease-free survival (DFS) rate was 90% with chemotherapy alone, whereas it increased significantly to 97.5% with the addition of blinatumomab. Similarly, in the SR-H group, the three-year DFS rate improved from 85% with chemotherapy alone to 94% with the combination treatment.

These findings indicate that for most pediatric B-ALL patients, standard chemotherapy combined with blinatumomab represents a new standard of care. For those who do not achieve an optimal or very good response with chemotherapy alone, the combination regimen is highly recommended.

Hematology Frontier: What are the primary safety concerns when using blinatumomab, such as neurotoxicity, cytokine release syndrome (CRS), and varying levels of toxicity?

Dr. Sumit Gupta: That’s an excellent question. I believe the answer can be divided into two aspects.

On one hand, as you mentioned, blinatumomab is associated with certain adverse events (AEs), including cytokine release syndrome (CRS) and neurotoxicity. However, the incidence of grade 3 or higher CRS or neurotoxicity was quite low, around 1% to 3%. Importantly, the patients enrolled in our study had a very low disease burden when receiving blinatumomab, which likely reduced the risk of these adverse effects.

On the other hand, it is important to note that all patients in this study were under 10 years old. Some research suggests that older children have a relatively higher risk of developing neurotoxicity. Therefore, our results should be interpreted with caution in this context. That being said, in our study, severe CRS and neurotoxicity were rare, which is reassuring.

Additionally, compared to chemotherapy alone, patients in the SR-A group who received chemotherapy plus blinatumomab had a higher risk of developing grade 3 sepsis or catheter-related infections. Interestingly, these infections did not occur during blinatumomab administration but rather in subsequent chemotherapy cycles. We are conducting further analyses to gather more insights, but we hypothesize that this could be related to the interaction between blinatumomab-induced B-cell depletion and chemotherapy effects. Fortunately, compared to chemotherapy alone, the proportion of patients who experienced grade 4 or 5 severe sepsis or infections did not increase with the addition of blinatumomab.

Hematology Frontier :Are there any plans for future research?

Dr. Sumit Gupta: That’s an excellent question. As I mentioned earlier, this study focused on pediatric B-ALL patients under 10 years old. Given the published results, I believe standard chemotherapy combined with blinatumomab has now become the new standard treatment for this patient population.

Meanwhile, earlier this year, another study published in The New England Journal of Medicine (NEJM) investigated the use of blinatumomab in adult B-ALL patients aged 30 to 70, with successful outcomes. However, there is currently a lack of data on patients aged 10 to 30. It is important to highlight that, at least in North America, older pediatric B-ALL patients generally receive a treatment regimen similar to the one used in our study. Therefore, it is difficult to assume that blinatumomab is effective in patients under 10 and over 30 but not in those aged 10 to 30. Nevertheless, further studies are necessary to bridge this gap.

Even more exciting is the fact that blinatumomab has demonstrated significant efficacy in preventing bone marrow relapses. This raises an important question: given its strong efficacy, can we reduce the intensity of chemotherapy? In our study, blinatumomab was added to the standard regimen without reducing chemotherapy. However, we are currently designing studies to explore whether reducing certain chemotherapy components while maintaining high efficacy is feasible, potentially mitigating chemotherapy-related short- and long-term adverse effects.

Finally, I would like to point out that blinatumomab has no activity in the central nervous system (CNS). Although the CNS relapse rate in our study was very low, there was no difference in CNS relapse rates between the chemotherapy-only group and the chemotherapy plus blinatumomab group. Thus, a future research direction would be to determine how to maintain high treatment efficacy while reducing chemotherapy and simultaneously preventing CNS relapses—something blinatumomab alone has not yet achieved.