Researchers Deliver Updates on Efforts Toward Eradicating CLL

Panelists provided a wide-ranging view of the current avenues being investigated to optimize the treatment of chronic lymphocytic leukemia (CLL), including minimal residual disease (MRD) assessment, combination regimens, and chimeric antigen receptor (CAR) T-cell therapy.

This session at the European Hematology Association (EHA) 2023 Congress was organized by the European Research Initiative on CLL (ERIC), a specialized working group of the EHA. It featured 3 experts recapping research on their chosen topic and offering insights on the most promising approaches to come.

First, Andy Rawstron, MD, PhD, of the Leeds Teaching Hospitals NHS Trust in the United Kingdom, answered the title of his presentation “Is MRD Assessment Necessary?” by explaining that while it’s not yet necessary in clinical practice, it is helpful in clinical trials for learning about kinetics. Across therapies and disease states, MRD can serve as a predictor of outcomes over the coming years, as patients with levels higher than 1% are likely to have short survival. CLL is a dynamic disease, with factors such as TP53 or IGHV mutation status affecting the association between MRD and outcomes, and it’s also important to think of MRD as a distribution of disease levels rather than a simple positive or negative answer, Rawstron said.

Despite these caveats, emerging research is looking into MRD as a rationale for when to stop treatment or when to add a Bruton tyrosine kinase (BTK) inhibitor to a venetoclax regimen. In terms of practicality, Rawstron recommended targeting a level of 1 leukemia cell in every 10⁵ white blood cells, and he noted that peripheral blood samples are easier to obtain than bone marrow samples.

In response to a question from session moderator Lydia Scarfò, MD, at Università Vita-Salute San Raffaele, Milano, Italy, about whether MRD assessment is ready for prime time in clinical practice, Rawstron said that “as soon as it’s required, we’ll need some training and certification that ERIC has also been closely involved in across the globe, but apart from that it’s ready to go whenever it’s needed.”

Next, Florence Cymbalista, MD, PhD, of Sorbonne Paris Nord in France, delivered a talk on which drug combinations can be helpful in CLL. Factors motivating the use of combinations are their potential to increase treatment efficacy, limit duration and toxicity, and allow response evaluation by MRD.

One promising approach is combining venetoclax and a BTK inhibitor, which are the most efficient targeted drugs on their own. Trials including GLOW and FLAIR are evaluating this approach, but Cymbalista noted there are not yet data on head-to-head comparisons. She is interested in seeing these direct comparisons in research to come, as well as results using second-generation BTK inhibitors that carry less toxicity than ibrutinib.

Given that clinical trial participants are often younger and healthier than real-world populations due to eligibility criteria, Cymbalista wants to see “collection of information from noneligible patients, and of course we need to integrate the biological knowledge into more personalized therapy.”

Lastly, Marco Ruella, MD, of Penn Medicine in Philadelphia, discussed the approach of harnessing immune cells’ potential via CAR T-cell therapy. The first 3 patients to receive CAR T therapy at Penn had CLL, but more recently the 6 FDA-approved therapies have not been indicated for this cancer. Ruella attributed this to the low complete response rate seen in several trials of CAR Ts in the disease, but noted “mindblowing” findings that CAR T cells were still seen circulating and keeping B cells to zero even 10 years after a single infusion.¹

“I think there is a lot of potential for CAR T cells because we can get deep responses and prolonged responses, but it doesn’t work for all patients,” he said.

Ruella also highlighted findings on combination treatment, including a 72% MRD-negative complete response rate in 19 patients who received ibrutinib and CTL119. Combining CART19 and venetoclax proved more challenging because the latter was killing the CAR T cells, but it could be possible to develop resistance to venetoclax by selecting for mutations.

Newer agents for CLL can prolong survival in some patients, Ruella said, “but I think it would be kind of nice to still shoot for a cure,” and CAR T-cell therapy is a promising approach to achieving that aim.

In fact, at a satellite symposium held earlier at the EHA 2023 Congress, he recounted, 67% of that audience asked about the most influential strategy in CLL in the next few years voted for the combination of CAR T and BTK inhibitor therapy.

Reference

1. Melenhorst JJ, Chen GM, Wang M, et al. Decade-long leukaemia remissions with persistence of CD4+ CAR T cells. Nature. 2022;602(7897):503-509. doi:10.1038/s41586-021-04390-6