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Medical Director of Hematology Research
Willamette Valley Cancer Institute
Jeff P. Sharman, MD, has disclosed that he has received funds for research support from AbbVie, AstraZeneca, Genentech, Gilead Sciences, Lilly, Pharmacyclics, and TG Therapeutics and consulting fees from AbbVie, AstraZeneca, Genentech, Lilly, Pharmacyclics, and TG Therapeutics.
Due to the lower incidence of chronic lymphocytic leukemia (CLL), community oncologists may make treatment decisions for only a few patients with CLL per year and thus may not be compelled to stay up to date with the latest developments in the field. However, we have seen an explosion in data informing treatment of this disease, with numerous approvals of targeted agents since 2015 and several additional drug approvals expected in the coming years. As such, there is a lot of “noise” in the field, and it is easy to get lost unless you have been paying attention. In this commentary, I review data from a survey of healthcare professionals (HCPs) that was conducted by Clinical Care Options (CCO) in collaboration with Christopher R. Flowers, MD, MS, and myself. This survey sought to assess practice trends and educational needs surrounding approved and investigational BTK inhibitor therapies for patients with CLL. I will offer my thoughts on this data and suggestions for approaches to managing patients with CLL with BTK inhibitors.
Survey Design and Demographics
A 2-part survey was conducted between November 2021 and January 2022 and included an online survey of US- and formerly US–based HCPs to determine their current approaches to practice, challenges that impact treatment decisions, and knowledge of emerging therapy options. In total, 475 HCP respondents to the online survey indicated that they manage patients with CLL, with 59% reporting that they were physicians (41% nurses, nurse practitioners, physician associates/physician assistants, or pharmacists) and 74% indicating that they manage ≤10 patients with CLL (and mantle cell lymphoma) per week. Thirty HCPs also were interviewed over the phone to provide additional commentary on factors that influence decision-making (70% physicians).
CLL Therapy Selection
The good news is that CLL may be easier to treat now than ever before. With novel agents available, many patients will never need chemoimmunotherapy, which was the standard of care before the approval of ibrutinib. Both BTK inhibitor– and venetoclax-based regimens have clearly demonstrated higher efficacy than traditional chemoimmunotherapy, and it is a relatively infrequent circumstance where chemotherapy would be appropriate.
Despite this, frontline therapy selection remains challenging for community HCPs, and decision-making can be a complex process. For example, of 270 respondents to the survey, 39% did not select preferred therapy (per expert recommendations) for a patient with CLL and atrial fibrillation requiring frontline treatment, and 13% would still recommend a chemoimmunotherapy regimen. Likewise, 47% were unable to select preferred therapy for a patient with CLL and high tumor burden and renal insufficiency requiring frontline treatment.
The most consequential decision for patients with CLL is often therapy for previously untreated disease. Here, the choice is between venetoclax plus obinutuzumab or BTK inhibitor–based therapy. Many patients prefer fixed-duration therapy with venetoclax plus obinutuzumab rather than indefinite therapy with a BTK inhibitor, but the simplicity of BTK inhibitors is hard to beat. Duration of therapy was an important decision point for frontline therapy selection for many survey interviewees. Many felt that their patients prefer fixed duration over ongoing therapy, especially younger patients (younger than 50 years), patients who want to avoid or delay an ongoing regimen, or, as a nurse practitioner observed, patients with “some sort of emotional barrier to taking a pill for the rest of their lives.” These HCPs used duration of therapy as a way to explicitly engage patients about their preferences for treatment.
I often consider whether the patient can navigate the logistical challenges of starting venetoclax plus obinutuzumab with the busy first month of obinutuzumab infusions and the second month of venetoclax ramp-up. Patients will have 5 infusion visits and more than a dozen lab draws in the first 2 months. Furthermore, some patients may have high tumor burden or compromised renal function, putting them at increased risk of tumor lysis syndrome complications with this regimen. By contrast, BTK inhibitors often are very easy to start, but they must be continued indefinitely. I often see patients who start on these agents once several weeks after starting, then every several months thereafter.
If selecting a BTK inhibitor, which should you use? Both ibrutinib and acalabrutinib are approved for treating CLL, and zanubrutinib will likely be approved in the coming months. The second-generation BTK inhibitors (acalabrutinib and zanubrutinib) each have been compared with ibrutinib and found to have fewer specific adverse events, including atrial fibrillation. Telephone interviewees reported a range of rationales for therapy selection in the presence of comorbidities. Of note, almost one half of interviewed community physicians said they would likely avoid using BTK inhibitors for patients with preexisting atrial fibrillation, bleeding history, or concurrent treatment with proton pump inhibitors or anticoagulation agents. They cited venetoclax plus obinutuzumab as their preferred option in these scenarios. Interviewees who said they mostly use ibrutinib in the frontline setting do so on the grounds that this agent has been approved for longer than other agents, is more likely to be reimbursed, or has a more forgiving dosing regimen (“obviously once a day is easier on a patient than twice a day”). Safety and tolerability were cited as the greatest advantages for selecting acalabrutinib over ibrutinib in the frontline CLL setting regardless of whether patients had preexisting comorbidities.
Should you add an anti-CD20 antibody to a BTK inhibitor? This varied among HCPs surveyed, with 13% indicating that they always add this therapy for any patient they plan to treat with ibrutinib or other BTK inhibitors. There are no data to indicate that this addition enhances the efficacy of ibrutinib or zanubrutinib, but when an anti-CD20 antibody is added to acalabrutinib, progression-free survival is improved (albeit with some increase in toxicity, including infusion reactions, neutropenia, and infections). For younger, healthier patients for whom long-term disease control is desired, it may make sense to add obinutuzumab to acalabrutinib. Although there are not any situations for which adding rituximab to a BTK inhibitor has been shown to improve outcomes, it might be considered in the setting of concurrent immune thrombocytopenic purpura or hemolytic anemia. It should be noted that anti-CD20 antibodies can reduce COVID-19 vaccination response and may worsen outcome if a patient acquires COVID-19, so anti-CD20 antibodies have been used less commonly in the recent past.
A significant percentage of surveyed HCPs were uncertain or lacked confidence in their approach to therapy selection for patients with relapsed/refractory CLL, with optimal sequencing identified as a primary concern. Interviewees in both academic and community practice settings generally relied on a guiding principle of switching therapy class or mechanism of action at relapse or progression and expressed uncertainty about sequencing BTKi therapies. One physician noted: “I don’t think we know exactly how to sequence. I think you choose what fits the patient most. I think the main difference in making the choice is cardiac events vs finite treatment.”
In my practice, we often recommend whichever regimen (BTK inhibitor– vs venetoclax-based therapy) was not used in the frontline setting. If a patient experiences disease progression while receiving therapy with a BTK inhibitor, it is often a good idea to have the next therapy lined up before discontinuing a BTK inhibitor, as there can be more symptomatic progression when a BTK inhibitor is discontinued.
Novel BTK Inhibitors and Clinical Trial Enrollment
Novel therapeutic strategies continue to emerge. For example, noncovalent BTK inhibitors are now in late-stage clinical trial development. First- and second-generation BTK inhibitors (eg, acalabrutinib, ibrutinib, and zanubrutinib) covalently bind to BTK; over time, patients may acquire mutations in BTK that result in them becoming resistant to covalent inhibitors. Pirtobrutinib (formerly known as LOXO-305) is a next-generation noncovalent BTK inhibitor that acts independently of residue C481, the site of covalent inhibitor binding and most frequently mutated residue among patients with BTK inhibitor resistance. The phase I/II BRUIN trial demonstrated that pirtobrutinib is effective in patients with relapsed/refractory CLL, with a similar high overall response rate among patients with CLL with and without BTK inhibitor resistance and/or the BTK C481 mutation and low rates of adverse events of special interest. Phase III clinical trials are currently enrolling with this agent. Nemtabrutinib is another noncovalent BTK inhibitor that has shown promise for treating CLL and currently is being studied in a phase II trial.
Despite the emergence of BTK inhibitor resistance as a concern in clinical practice, few interviewees considered mutational resistance as a factor in therapy selection in the relapsed/refractory setting. Many HCPs were unfamiliar with BTK inhibitor mechanisms of action, with 46% of online survey respondents uncertain about the noncovalent mechanism of pirtobrutinib and only 33% aware that pirtobrutinib has shown activity in patients with CLL and disease progression on ibrutinib due to the appearance of a BTK C481 resistance mutation. With only 40% of survey respondents indicating that they would recommend a newly approved or investigational agent if they were unfamiliar with the class or mechanism of action, this indicates an area of educational need.
Additional emerging strategies include combination therapy with BTK and BCL-2 inhibitors, measurable residual disease–guided therapy, novel PI3 kinase inhibitor strategies, bispecific antibodies, and CAR T-cell therapy. Knowledge of investigational strategies and ongoing trials is important, as clinical trials should be considered for all patients with CLL, but this can be challenging in practice. Telephone interviewees at tertiary care centers with “good access” to clinical trials or research nurses to support eligibility screening said they discussed trial participation as a treatment option at diagnosis and again at disease progression. However, few interviewees overall felt they had good access to clinical trials. Most also viewed their patients as ineligible for trial enrollment or unable to travel to participate in a clinical trial. They tended to offer clinical trial participation as an option in the relapsed/refractory setting. Some HCPs felt that because there are effective options available as standard of care for frontline therapy, clinical trials are less of a consideration until later lines of therapy.
What aspects of managing patients with CLL do you find the most challenging? Answer the polling question and join the conversation by posting a comment in the discussion section below.
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