Monotherapy for CLL

Many patients with chronic lymphocytic leukemia (CLL) are treated with two- or three-drug regimens, but for some patients just one drug may be enough. Particularly for older patients or those who are less able to travel to a clinician’s office, monotherapy may better suit their therapeutic needs and lifestyles.

Monotherapy is a common approach in CLL, with several targeted therapies, such as venetoclax (Venclexta), ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa), receiving FDA approval as monotherapy. Bruton’s tyrosine kinase (BTK) inhibitors, including ibrutinib, acalabrutinib, and zanubrutinib, are used in the relapsed or refractory setting, and also as first-line treatment.

The initial report of monotherapy with the BCL-2 inhibitor venetoclax showed it had durable clinical activity and favorable tolerability in patients with relapsed or refractory CLL whose disease had progressed during or after discontinuation of ibrutinib. Venetoclax also showed deep and durable responses in relapsed/refractory CLL in the open-label, single-arm, phase IIIb VENICE-1 trial, including in patients who had previously been treated with BTK or PI3K inhibitors. Venetoclax is less used as monotherapy today, and is particularly effective when combined with anti-CD20 antibodies, such as obinutuzumab (Gazyva) or rituximab (Rituxan).

“Monotherapy for CLL patients is a simple, effective treatment option for some patients. It’s convenient if the patient doesn’t live near a treatment center, and it is tolerated well by almost all patients,” said Andrew Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City. “BTK inhibitors can be administered to older patients with substantial benefit.”

For older patients with less ability to travel, snow birds who do not want to come home for treatment, and those who want to avoid infusions of monoclonal antibodies or chemotherapy drugs administered intravenously, BTK inhibitor monotherapy may be the best option, he said.

Clinical Comparisons

In a clinical trial comparing acalabrutinib to ibrutinib in previously treated CLL patients with high-risk features, acalabrutinib demonstrated noninferior progression-free survival (PFS) while showing a lower risk of certain adverse events, including atrial fibrillation and hypertension. In previously treated CLL patients, the ELEVATE-RR trial showed a similar PFS in both arms, but acalabrutinib had fewer cardiovascular and bleeding events.

The phase III ALPINE trial compared zanubrutinib with ibrutinib in patients with relapsed/refractory CLL or small lymphocytic lymphoma. The trial demonstrated zanubrutinib is superior in terms of PFS, with a statistically significant and clinically meaningful benefit compared to ibrutinib, reducing the risk of progression by 32% in the final analysis. The overall response rate was higher with zanubrutinib (85.6%) compared to ibrutinib (75.4%), and responses deepened over time. Zanubrutinib also had lower rates of cardiac adverse events, including atrial fibrillation, compared to ibrutinib.

Considerations for Monotherapy

Monotherapy can be effective in treating CLL, but combination therapies may offer higher rates of minimal residual disease-negative remission and delay disease resistance. While monotherapy can be well-tolerated, some medications, like BTK inhibitors, can have specific side effects that need to be monitored and managed, including bleeding, bruising, infections, diarrhea, and cardiovascular issues such as atrial fibrillation and hypertension.

“Older patients may see more bruising than younger patients because they have less subcutaneous fat and are already more sensitive to bruising from minor trauma,” Zelenetz said. He pointed out that all BTK inhibitors cause inhibition of platelet aggregation and therefore may lead to bruising.

Continuous BTK inhibitor therapy can also lead to the development of resistance mutations, highlighting the importance of fixed-duration treatment or combination therapies. Continuous monotherapy with targeted therapies can be expensive, and adherence to treatment regimens may be a factor.

“Monotherapy in CLL is like taking blood pressure medication in that there is no endpoint, which is an unusual way to treat most cancer patients. This is continuous, not time-limited, therapy. We stop the drug when it stops working or the patient develops intolerable side effects,” Zelenetz said.

Individualized Approach

The best treatment strategy for CLL, including the choice between monotherapy and combination therapies, should be determined on a case-by-case basis, considering the patient’s individual characteristics, disease stage, and response to prior treatments. “The choice of therapy should be a shared decision after a conversation with the patient,” Zelenetz said.

Patient goals are important. “How the patient feels about therapy plays a significant role in choosing medication,” said Jennifer Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston. “Younger patients may want a treatment that achieves a deep remission and then stop therapy. Older patients may not want to go to the clinic frequently for treatment.”

Kerry Rogers, MD, of the Ohio State University Comprehensive Cancer Center in Columbus, agrees that “older, less-fit patients mostly don’t want two drugs. More drugs always mean more side effects. Patients in their 80s and 90s who have other health problems and have trouble getting to appointments don’t need multiple drugs. The very elderly in a care facility with mild cognitive impairment have a real risk to coming to the clinic for multiple appointments. It’s better to give them a BTK inhibitor.”

She prefers acalabrutinib or zanubrutinib due to the more favorable cardiovascular safety profile.

For monotherapy, Zelenetz usually prescribes zanubrutinib, which he has studied and used in many CLL patients. “Zanubrutinib is a good first-line, oral treatment. I see patients intensely for the first month to make sure they tolerate zanubrutinib and do not develop a bad rash, diarrhea, or bruising.”