Should Patients With CLL Take Breaks From BTK Inhibitors?

HOUSTON — Bruton’s tyrosine kinase inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib have revolutionized the treatment of chronic lymphocytic leukemia (CLL). But should patients take a break from them?

At the Society of Hematologic Oncology (SOHO) 2024, two hematologist-oncologists — Inhye Ahn, MD, of Dana-Farber Cancer Institute in Boston, and Kerry A. Rogers, MD, of The Ohio State University in Columbus, Ohio — faced off in a debate. Ahn said the drugs can indeed be discontinued, while Rogers argued against stopping the medications.

“When I talk to my own patient about standard-of-care options in CLL, I use the analogy of a marathon and a sprint,” Ahn said. A marathon refers to continuous treatment with Bruton’s kinase inhibitors given daily for years, she said, while the sprint refers to the combination of venetoclax with an anti-CD20 monoclonal antibody given over 12 cycles for the frontline regimen and 2 years for refractory CLL.

“I tell them these are both considered very efficacious regimens and well tolerated, one is by IV [the venetoclax regimen] and the other isn’t [Bruton’s kinase inhibitors], and they have different toxicity profile. I ask them what would you do? The most common question that I get from my patient is, ‘Why would anyone do a marathon?'”

It’s not solely the length of treatment that’s important, Ahn said. She pointed out that toxicities from the long-term use of Bruton’s kinase inhibitors build up over time and can lead to hypertension, arrhythmia, and sudden cardiac death.

In addition, she said, infections can occur, as well as hampered vaccine response, an important risk in the era of the COVID-19 pandemic. The cost of the drugs is high and adds up over time, she said, and continuous use can boost resistance.

Is there a way to turn the marathon of Bruton’s kinase inhibitor use into a sprint without hurting patients? The answer is yes, through temporary discontinuation, Ahn said, although she cautioned that early cessation could lead to disease flare. “We dipped into our own database of 84 CLL patients treated with ibrutinib, and our conclusion was that temporary dose interruption or dose reduction did not impact progression-free survival,” she said.

Moving forward, she said, “more research is needed to define the optimal regimen that would lead to treatment cessation, the optimal patient population, who would benefit most from the cessation strategy, treatment duration, and how we define success.” For her part, Rogers argued that the continuous use of Bruton’s kinase inhibitors is “really the most effective treatment we have in CLL.”

It’s clear that “responses deepen with continued treatment,” she said, noting that remission times grow over years of treatment. She highlighted a 2022 study of patients with CLL who took ibrutinib that found complete remission or complete remission with incomplete hematologic recovery was 7% at 12 months and 34% at 7 years. When patients quit taking the drugs, Rogers said, “you don’t get to maximize your patient’s response to this treatment.”

She also noted that the RESONATE-2 trial found that ibrutinib is linked to the longest median progression-free survival of any CLL treatment at 8.9 years. “That really struck me a very effective initial therapy.”

Indeed, “when you’re offering someone initial therapy with a Bruton’s kinase inhibitor as a continuous treatment strategy, you can tell people that they can expect a normal lifespan with this approach. That’s extremely important when you’re talking to patients about whether they might want to alter their leukemia treatment.”

Finally, she noted that discontinuation of ibrutinib was linked to shorter survival in early research. “This was the first suggestion that discontinuation is not good.”

Rogers noted that discontinuing the drugs is sometimes necessary due to adverse events, but patients can “certainly switch to a more tolerable Bruton’s kinase inhibitor. With the options available today, that should be a strategy that’s considered.”

Audience members at the debate were invited to respond to a live online survey about whether Bruton’s kinase inhibitors can be discontinued. Among 49 respondents, most (52.3%) said no, 42.8% said yes, and the rest were undecided/other.

Disclosures for the speakers were not provided. Ahn disclosed consulting for BeiGene and AstraZeneca. Rogers disclosed receiving research funding from Genentech, AbbVie, Janssen, and Novartis; consulting for AstraZeneca, BeiGene, Janssen, Pharmacyclics, AbbVie, Genentech, and LOXO@Lilly; and receiving travel funding from AstraZeneca.

Randy Dotinga is an independent writer and a board member of the Association of Health Care Journalists.