Understanding CLL And SLL Treatment Evolution

By Erin Harris, Editor-In-Chief, Cell & Gene
Follow Me On Twitter @ErinHarris_1

Dr. Neal Flomenberg, Chief Science Officer and Head of Research and Development, and Dr. Dolores Grosso, Clinical Development Lead, make an exceptional team at Tevogen Bio. Their strong rapport and shared commitment to advancing patient care drive a seamless collaboration between scientific innovation and clinical execution. Dr. Flomenberg’s deep expertise in immunology and translational research pairs perfectly with Dr. Grosso’s clinical insight and hands-on experience guiding novel therapies through development.

I had the good fortune to speak with both experts about the shifting landscape in treating chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) (i.e., the tissue version of CLL). Together, Dr. Flomenberg and Dr. Grosso embody Tevogen Bio’s mission to make cutting-edge, personalized immunotherapies more accessible, turning scientific vision into meaningful impact for patients.

From Chemotherapy to Targeted Therapy

Dr. Flomenberg opened our discussion by defining CLL and SLL. These conditions, most commonly diagnosed in older adults, were once managed primarily through chemotherapy or, in rare cases among younger patients, stem cell transplantation. “CLL and SLL are chronic and usually slow-moving malignancies. They’re most common in older individuals,” he said. Reflecting on past standards, he noted, “This is one of the examples where targeted treatment has changed everything. Chemotherapy is rarely used now and stem cell transplant almost never.”

He traced this transformation to the discovery of Bruton’s tyrosine kinase (BTK), a gene essential for B cell development, referencing its namesake, Dr. Ogden Bruton, and the 1993 genetic breakthrough that opened the door to this group of targeted therapies. Following the cloning of the BTK gene, the development and approval of BTK inhibitors, (i.e., ibrutinib (2013), acalabrutinib (2017), and zanubrutinib (2020), fundamentally changed patient care. These agents bind covalently through a specific cysteine residue in the adenosine triphosphate (ATP) binding site. “This is an example of a disease that’s shifted from chemotherapy and very aggressive approaches to targeted therapy, and much more tolerable therapy, over the course of the last several decades,” Dr. Flomenberg said.

The Promise and Complexity of Jaypirca

Dr. Grosso discussed the next-generation BTK inhibitor pirtobrutinib, marketed as Jaypirca and developed by Eli Lilly. She emphasized its current approval for third-line mantle cell lymphoma and its emerging data in CLL/SLL. “Jaypirca has an indication, or a label, for mantle cell lymphoma, but it’s in third-line therapy,” she explained. “Based on recent studies, it appears that the drug is promising for a more front-line approach in CLL/SLL.

What sets Jaypirca apart is its non-covalent binding, which helps avoid resistance mutations that plague other BTK inhibitors. “Permanently bound BTK inhibitors can become inactive due to a mutation at the covalent binding site. Jaypirca binds in a different way, so that this mutation doesn’t affect it,” Dr. Grosso said. She added that this property could support its use in frontline therapy for CLL, particularly in patients whose mutations render covalent BTK inhibitors ineffective.

Dr. Grosso reviewed a trio of Phase 3 BRUIN trials. One, BRUIN321, compared Jaypirca against traditional options such as rituximab-idelalisib and rituximab-bendamustine for previously treated patients. “It showed a highly statistically significant p value in  improvement in progression-free survival in favor of Jaypirca,” she said, noting that median PFS extended from 8.7 to 14 months.

Another trial in treatment with Jaypirca is performing comparably to established therapies, though overall survival data are still maturing. “Jaypirca compared favorably in terms of progression-free survival to many other agents,” Dr. Grosso said. “It was not inferior to ibrutinib, which is frontline. Is it better? We don’t know yet.”

Importantly, Jaypirca’s greatest advantage may be as a rescue therapy for patients who develop resistance mutations on other BTK inhibitors. “Jaypirca provides a very important backup treatment regimen for patients that develop that cysteine 481 mutation on ibrutinib,” Dr. Grosso said. She also highlighted ongoing research exploring combinations of covalent and non-covalent BTK inhibitors that may further change the treatment landscape.

Navigating New Choices for Patients

Dr. Flomenberg emphasized the practical implications for patients. “These agents have been and will continue to be exceedingly important,” he said. “Standard chemotherapy can have significant side effects, and that put some limits on how far you can go in terms of age.” He praised the impact these therapies have had on older patients, noting the decline in toxicities versus older treatment approaches.

Both experts discussed how individual risk factors, personality, and patient values come to the forefront as more therapeutic options become available and how crucial patient participation is in shared decision-making. “There are some patients who just feel most comfortable if they receive the tried-and-true, established course of action with all the data, and not something brand new,” Dr. Flomenberg said. “And then there’s another subset who prefers the latest and greatest. To some extent, you present the issues, and while you certainly don’t lay the whole decision on the patient, you encourage them to be a participant in their care decisions.”

Dr. Grosso added that discontinuation rates and side effect profiles must also factor into real-world treatment decisions. “In the BRUIN321 trial, Jaypirca had a discontinuation rate of 17.2 percent, significantly lower than older regimens,” she said. “Any treatments that become more targeted and have fewer side effects will play a big role in modulating treatment algorithms, especially in a disease where there are many choices. It’s a mix of things: cost, scientific literature, and how this drug helps me in terms of my day-to-day living.”

Expanding the Platform to Viruses and Cancer

Shifting from CLL/SLL to immunotherapy platforms for viruses, cancer, and beyond, Dr. Flomenberg described Tevogen Bio’s development and clinical validation of a platform based on antigen-specific T cells. Indeed, Tevogen Bio’s antigen-specific T cell platform represents a scalable, non-genetically modified immunotherapy that bridges proven clinical safety with new applications in infectious disease and oncology. “More than 500 patients in the published medical literature have received T cells after bone marrow transplant (BMT) or stem cell transplant, demonstrating a strong pattern of efficacy and safety,” he said.

Dr. Grosso explained the manufacturing process, which begins with healthy donor cell apheresis. “In the lab, we “train” the cells to go after the viral targets we’re pursuing,” she said. The approach is highly flexible and applicable across targets such as Epstein–Barr virus, human papillomavirus, and hepatitis B. And because it uses no genetic modification, it remains cost-effective and scalable. “Our platform is very flexible, and there’s no genetic modification, so the cost is low, we get more doses, and it’s extremely precise,” she added.

Dr. Flomenberg provided a compelling example from their proof-of-concept trial treating high-risk and immunocompromised COVID-19 patients. “We walked into the room of the first patient on Day 3, and our patient said, ‘Doc, I felt so much better starting last night. I feel like I’m completely back to normal at this point,’” he recalled. “That patient’s day 4 post-treatment nasal swab PCR came back negative. I didn’t say anything to anyone until the day 7 specimen confirmed the early negative result at which point I was certain that we had something special. There was a little variation from patient to patient as the study went on.  There were some additional patients who cleared their virus by day 4.  In the aggregate, all patients eliminated 99% of the virus by day 14, and ten of the twelve eliminated 100% of the virus by day 14.  Of note, six of the twelve patients we treated were immunocompromised, two of whom immediately underwent stem cell transplant without complications.” 

Building on Safety and Looking Ahead

Both experts stressed the importance of rigorous trial designs that protect high-risk and immunocompromised populations. “In very high-risk patients, you really can’t do placebo trials,” Dr. Flomenberg explained. “We think that, with the right trial design, we can treat people safely, still garner meaningful information from the trial, and hopefully push this along further.”

The Road Ahead for Precision Therapies

The development of non-covalent BTK inhibitors such as Jaypirca and advances in targeted T cell platforms such as Tevogen’mark a new era in cancer and infectious disease management. Real-world data, evolving evidence, and patient priorities will guide future standards, ensuring innovation remains tightly linked to clinical reality.

“The bone marrow transplant experience and the COVID study have helped us believe that safety has already been established for Tevogen’s approach, which lays a solid foundation for broader application and benefit,” Dr. Flomenberg concluded.