Quest to Advance CLL Therapy Operating on Multiple Fronts

Therapeutic solutions for CLL, which remains incurable, are a work in progress | Image Credit: NicoElNino - stock.adobe.com

Although important new therapies have displaced chemoimmunotherapy as the first-line treatment for chronic lymphocytic leukemia (CLL), therapeutic solutions for the incurable cancer type remain a work in progress.

However, there are several potential new therapies on the horizon that could soon constitute meaningful options for patients with relapse after treatment, according to a new review published in OncoTargets and Therapy.

The study authors began by reviewing the advances that led to the current treatment paradigm. They said B-cell receptor signaling and intrinsic apoptotic resistance are key to the development of CLL cells, and thus efforts to target those pathways have been widely studied.

The 2 biggest changes in the treatment of CLL in the past decade have been covalent Bruton tyrosine kinase (BTK) inhibitors and the selective B-cell lymphoma 2 (BCL2) inhibitor, venetoclax (Venclexta; Abbvie/Genentech).

“These targeted therapies have dramatically transformed the treatment landscape of CLL and long-term survival can be achieved for many patients even those with high-risk features such as TP53 disruption and complex karyotypes,” the authors noted.

Yet, they said even patients who respond well to these therapies will eventually see their cancers progress.

“In this situation, they have limited treatment options with poor clinical outcomes, which highlights a significant unmet medical need,” they wrote.

They then outlined some of the latest research into novel agents with distinct mechanisms that have been developed for CLL and shown promise.

One area of research has focused on noncovalent BTK inhibitors, including pirtobrutinib (Jaypirca; Eli Lilly) and nemtabrutinib. The former was approved last year by FDA for third-line or later treatment of CLL or small lymphocytic leukemia. These therapies play off the fact that the most common secondary resistance mechanisms to covalent BTK inhibitors are BTK C481 mutations.

“Therefore, novel agents that noncovalently bind to BTK at non-C481 sites have been developed with promising clinical efficacy,” the authors wrote.

Another promising category of emerging therapy is that of BTK degraders, which aim to break down the BTK protein rather than inhibit its function. Several such therapies are currently under investigation, the authors wrote, and although data are preliminary, the early results have been encouraging.

Other approaches under investigation include immunotherapies, such as bispecific antibodies (bsAbs) and chimeric antigen receptor (CAR) T cells. The former work by redirecting T cells to tumor cells, the authors explained, “leading to potent tumor cell lysis.” Among the bsAbs under investigation in hematological malignancies like CLL are blinatumomab, a CD3/CD19 bispecific T-cell engager, and epcoritamab, a CD3/CD20 bsAb that redirects and activates T cells to kill CD20-expressing tumor cells.

CAR T cells have led to strong outcomes in some other types of hematological malignancies, leading to the study of those therapies in CLL, the authors said. However, there are still several hurdles to overcome to make the therapy successful in CLL, which the authors said is one reason why combination strategies are being investigated.

They noted one way to speed up the clinical application of emerging treatments is to do more research into potential biomarkers that could help identify the best patients and best treatment sequences for the new therapies.

“Furthermore, effective collaboration among academia, industry, regulatory agents, and patients in multiple regions is increasingly important to efficiently conduct patient-centered clinical trials of novel treatments for CLL,” they concluded.

Reference

Hayama M, Riches JC. Taking the next step in double refractory disease: current and future treatment strategies for chronic lymphocytic leukemia. Onco Targets Ther. 2024;17:181-198. doi:10.2147/OTT.S443924