Looking Back on the Transformation of CLL Treatment: Jeff Sharman, MD

Chronic lymphocytic leukemia (CLL) treatment has undergone a remarkable transformation over the past decade, shifting from a treatment landscape dominated by chemoimmunotherapy to one increasingly defined by targeted therapies. As clinicians gain more experience with these agents, the focus is now turning toward how best to combine and sequence therapies while continuing to improve long-term outcomes for patients.

In an interview with Targeted Oncology^TM following World CLL Day on September 1, Jeff Sharman, MD, chair, Lymphoma Research Executive Committees, SCRI at Willamette Valley Cancer Institute & Research Center, discussed the evolution of CLL treatment, remaining unmet needs, and emerging approaches that could shape the future of care.

Targeted Oncology: What have been some of the key advancements in CLL treatment over the past few years?

Jeff Sharman, MD: CLL has been utterly transformed in the last decade from a disease managed exclusively by chemoimmunotherapy, to a field now where chemoimmunotherapy has been almost entirely replaced by novel targeted therapies; those go after Bruton tyrosine kinase [BTK], BCL2, and then the immunotherapy targets of CD20. In more recent years, we're learning how to assemble these drugs into multi-drug regimens that can yield the most impressive outcomes. Whether that's a BTK [inhibitor] with a BCL2 [inhibitor] or a BCL2 with a CD20[-directed therapy] or triplet therapy including all 3 of them, we're learning how and where to use these regimens optimally. What's exciting to see is that among selected patients who start therapy for CLL, age-matched controls now show we’re no longer seeing a negative impact of CLL on overall mortality rates. I think what that means is we're bringing patients' outcomes up close to their age-matched controls, and while that is with therapy—we'd love to move away from therapy to the extent that we can—I think doing so with novel targeted therapies really has alleviated a lot of the burden of treatment on patients in the last handful of years.

What unmet needs still exist in the patient population?

My biggest concern remains of the patients who develop resistance to BTK inhibitors. These patients oftentimes have less favorable outcomes with subsequent therapies, and it's one of the reasons why I am pushing as hard as we can for multi-agent regimens because I think that we do see lower rates of BTK resistance. Those patients with BTK resistance do have an expanding menu of options, ranging from noncovalent BTK inhibitors such as pirtobrutinib [Jaypirca] and maybe nemtabrutinib sometime soon, but we're also seeing the introduction of BTK degraders. These look to be very active molecules that can eliminate the BTK enzyme, not simply inhibit it. These agents are not yet approved by the FDA, but I think they likely will gain regulatory approval at some point down the road. We also have additional BCL2 inhibitors that are forthcoming, such as sonrotoclax [Beqalzi], potentially also lisaftoclax. How we assemble these regimens will be one of the tasks for the field.

Even beyond that, I think that there are areas of further target innovation. I think that that we may see antibodies against novel targets in in CLL, potentially bispecifics as well, which have been harder to develop in CLL because of the [adverse] effects of bispecifics. There appears to be more cytokine release syndrome, but we may have the opportunity to test these in the consolidation setting, much like we do in large cell lymphoma, or perhaps other novel bispecific antibodies may find unique niches. Chimeric antigen receptor [CAR] T-cell therapy is relatively new, and I would say relatively underutilized in CLL, in part because we've done so well with targeted therapies; we don't have as much need for CAR T-cell therapy in CLL. However, I've had a number of patients who have been treated with CAR T-cell therapy, many of whom are now multiple years out with no evidence of disease, and it's encouraging because we know that these therapies can be curative in other settings. We just don't know yet in CLL if that's the case, and how long we would have to wait before we would feel confident saying something like that is hard to know.

Looking ahead, what developments are you personally excited about as the treatment landscape evolves?

In a shameless self-plug, I'm looking forward to releasing a book in the next month and a half on the history of CLL that tells the entire story of how we got to where we are today. I think it's going to elevate the patient experience with those patients who have the disease to really understand it in a more thorough context, and provide a foundation for patients to grow and extend their knowledge.

In terms of what I'm looking forward to in the development space, I’m definitely looking forward to updates from the CLL17 study [NCT04608318] that help us understand which of the different treatment approaches might be optimal for patients with different molecular characteristics. The MAJIC study [NCT05057494] is also doing the same, but with a novel BTK inhibitor, and I would be hopeful that we could see the approval for sonrotoclax in CLL sometime in the coming years as well.

FAQs

How has CLL treatment changed in recent years? CLL treatment has shifted from chemoimmunotherapy to targeted therapies, particularly agents targeting BTK, BCL2, and CD20. Clinicians are now studying how to best combine and sequence these therapies, including BTK/BCL2 combinations and triplet regimens.

What is the difference between covalent and noncovalent BTK inhibitors? Covalent BTK inhibitors bind irreversibly to the BTK enzyme, while noncovalent BTK inhibitors bind reversibly and can retain activity against some forms of BTK inhibitor resistance. Sharman highlighted pirtobrutinib as an example of a noncovalent BTK inhibitor being used for patients with resistant disease.

What are BTK degraders, and how could they be used for CLL treatment? BTK degraders are investigational therapies that eliminate the BTK protein rather than simply inhibiting its activity. Sharman described these agents as a promising approach for patients with BTK inhibitor-resistant CLL, although they are not yet FDA approved.

What is the role of CAR T-cell therapy in CLL? CAR T-cell therapy remains relatively new and underused in CLL, in part because targeted therapies have been highly effective. However, Sharman noted that some patients treated with CAR T-cell therapy have remained disease-free for several years, raising questions about its potential for durable, possibly curative responses in CLL.