CLL Treatment Landscape for the Community Oncologist

Mazyar Shadman, MD, MPH Fred Hutchinson Cancer Center | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

Key Points

• For patients with chronic lymphocytic leukemia (CLL), shared decision making based on patient preferences is key for choosing between time-limited venetoclax-based therapy and continuous Bruton’s tyrosine kinase (BTK) inhibitor therapy.

• Acalabrutinib and zanubrutinib are preferred BTK inhibitors over ibrutinib in the frontline setting.

• For patients with double-refractory CLL, pirtobrutinib plus lisocabtagene maraleucel are the standard follow-up options.

Treatment Algorithm for CLL

The cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, discussed the current treatment landscape of CLL for community oncologists with guest expert, Mazyar Shadman, MD, MPH, of Fred Hutchinson Cancer Center.

Screening Newly Diagnosed Patients With CLL

CLL can be asymptomatic, and not every newly diagnosed patient needs to immediately start treatment, even if they have high-risk disease features like TP53 mutation or deletion 17p (del[17p]). The standard practice is to initiate therapy once the patient meets International Workshop on CLL criteria. This paradigm might be impacted by the EVOLVE trial, which is exploring early intervention in patients with high-risk features, Dr. Shadman said.

When patients meet the threshold for initiating therapy, fluorescence in situ hybridization, conventional karyotyping, and IGHV mutation analyses should be performed to further define the risk factors. In addition to disease analyses, patient comorbidities should be identified, particularly cardiovascular risk factors or bleeding disorders, both of which can affect treatment choice. Patients’ social and support statuses can also influence treatment selection, as some therapies require frequent visits to the clinic.

Time-Limited Versus Continuous Therapy in CLL

When discussing first-line treatment options, the main question is whether fixed-duration therapy with a venetoclax-based regimen or continuous therapy with a BTK inhibitor is a better fit for a patient. Compared with continuous therapy with a BTK inhibitor, fixed-duration therapy has increased logistical demands including weekly clinic visits for eight weeks. In the community setting, the norm is for more patients to opt for continuous BTK inhibitor therapy, Dr. Shadman noted.

If the time-limited route is chosen, the FDA approved option is venetoclax plus obinutuzumab based on the phase 3 CLL14 study, although data from the AMPLIFY study may lead to the approval of venetoclax plus acalabrutinib. Time-limited therapy is not preferred in patients with TP53 alterations, as continuous BTK inhibitor therapy is associated with longer durations of remission. 

If continuous BTK inhibitor therapy is selected, there are three approved covalent BTK inhibitors in the first line, the first-generation agent, ibrutinib, and the second-generation agents, acalabrutinib and zanubrutinib. Ibrutinib has largely been dropped in favor of the second-generation BTK inhibitors whenever they are available. There are no direct head-to-head trials comparing zanubrutinib and acalabrutinib, but based on indirect comparisons and existing data, zanubrutinib may be slightly advantaged in the first-line setting, according to Dr. Shadman. 

Side Effects of Second-Generation BTK Inhibitors

Both second-generation BTK inhibitors are well tolerated, with slight variations in their safety profiles. Headaches are reported early after initiating acalabrutinib, although they are limited and well controlled with over-the-counter medication. In the ALPINE trial, zanubrutinib showed a signal for increased risk of hypertension. Oncologists should partner with other healthcare providers for each patient to aggressively control any hypertension with a multi-drug strategy. If a patient is not tolerating one BTK inhibitor well, data support that switching to a different BTK inhibitor can be an effective strategy.

Beyond Upfront  CLL Therapy

For patients who have progressive or refractory disease during or shortly after venetoclax-based therapy, the standard strategy is to switch to continuous covalent BTK inhibitor therapy, and vice versa for patients who progress while on continuous BTK inhibitor therapy. If a patient is refractory to both covalent BTK inhibitors and venetoclax-based regimens, the standard follow up treatment options are the noncovalent BTK inhibitor, pirtobrutinib, and the chimeric antigen receptor T (CAR-T)-cell therapy, lisocabtagene maraleucel. 

These two therapies should be considered as a combination approach and pursued in parallel. Pirtobrutinib typically achieves a limited-duration response while CAR T is associated with better outcomes in patients with more controlled disease. Therefore, using pirtobrutinib to maximize disease control while the CAR-T product is being produced is optimal, Dr. Shadman explained. 

The Role of MRD in CLL

Wrapping up the discussion, the doctors touched on the role of minimal residual disease (MRD) in CLL therapy. In his practice, Dr. Shadman checks MRD status in patients who complete fixed-duration therapy, although he routinely does not pursue additional therapy even if a patient is MRD-positive. “I don’t think we have strong evidence to suggest that continuing [treatment] beyond that end point would benefit the patient,” he said. Likewise, he felt there is no currently apparent role for MRD-guided treatment alterations in patients on continuous BTK inhibitor therapy.