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BTK inhibitors tend to produce better outcomes than standard chemoimmunotherapy regimens in the treatment of patients with newly diagnosed chronic lymphocytic leukemia (CLL), making these drugs a favorable option for frontline therapy, according to Dr. Susan O’Brien.

The first study results that support this stance came from the phase 3 RESONATE-2 trial, which compared Imbruvica (ibrutinib) with Leukeran (chlorambucil) in patients aged 65 years or older whose disease was not treated yet. With the longest follow-up of any BTK inhibitor trial in CLL, now out to seven years, the results showed that the average progression-free survival (PFS) – meaning the time that patients survived without their disease getting worse – had not been reached with Imbruvica. Moreover, at 6.5 years, 61% of patients on Imbruvica were progression free and alive vs 9% of patients on Leukeran.

“Very importantly, the patients with 11q deletion (del(11q)) appear to be doing somewhat better (with Imbruvica vs Leukeran) and they’re certainly not looking like a high-risk group. Additionally, there’s no difference in outcome by mutation status still with seven years of follow-up,” said O’Brien, the associate director for Clinical Research in the Chao Family Comprehensive Cancer Center and the medical director of the Sue and Ralph Stern Center for Cancer Clinical Trials and Research at UC Irvine Health.

 aberrations – a genetic mutation that can make CLL less responsive to chemoimmunotherapy – appear to derive significant benefit with Imbruvica, said O’Brien, who cited data from research that reflected a four-year PFS rate of 79%.

“Venclexta (venetoclax) is nowhere near as good (as Imbruvica) in this population,” added O’Brien, who is also a professor in the Division of Hematology/Oncology of the Department of Medicine at UC Irvine Health.

Patients with del(11q) represent another historically high-risk group. However, these patients too experience benefit with frontline Imbruvica, said O’Brien, who called attention to an integrated analysis of more than 1,000 patients that showed that those with del(11q) experienced a 42-month PFS rate of 70% vs 65% in those without del(11q).

“Not only is del(11q) not unfavorable anymore, but it’s actually favorable with (Imbruvica),” said O’Brien. “(

 and del(11q)) are two high-risk subsets that are not really high risk anymore (with BTK inhibitors), which is important.”

The phase 3 ELEVATE-TN trial is another example of why BTK inhibitors should be used up front, explained O’Brien. The study randomized patients to Calquence (acalabrutinib) alone, Calquence plus Gazyva (obinutuzumab), or Gazyva plus Calquence.

The four-year PFS rate was 78% with Calquence monotherapy, 87% with Calquence plus Calquence, and 25% with Calquence plus Calquence. Among patients with 17p deletion del(17p) and/or mutated 

, the four-year PFS rates were 76%, 75% and 18%, respectively. Among patients with unmutated 

, the four-year PFS rates were 77%, 86% and 4%, respectively.

Acknowledging that chemoimmunotherapy is not the only alternative to BTK inhibitors, O’Brien turned her attention to the phase 3 CLL14 trial, which compared Venclexta plus Calquence with chlorambucil plus Calquence.

Although time-limited therapy has garnered significant interest as an alternative to continuous treatment with BTK inhibitors, O’Brien explained that she is not as convinced that it’s such a home run, particularly in terms of efficacy.

According to updated results of the CLL14 trial, the four-year PFS rate was 74.0% with Venclexta/ Gazyva vs 35.4% with Leukeran/Gazyva.

Although O’Brien said that the overall PFS looks “pretty good” at four years, when broken by TP53 and IGHV status, it becomes apparent that patients with TP53 aberrations and unmutated IGHV perform significantly worse with Venclexta/Gazyva than the same populations on BTK inhibitors, explained O’Brien.

In CLL14, patients with TP53 aberrations and unmutated 

 experienced a median PFS of 49 months and 57.3 months, respectively.

“The four-year PFS for del(17p) on ibrutinib is 79%, which is a heck of a lot better than what (we’re seeing with Venclexta/Gazyva),” said O’Brien.

Moreover, although patients with unmutated 

 did “pretty well” with Venclexta/Gazyva at four years, the same population on Calquence/Gazyva experienced a four-year PFS rate of 86%.

“Patients who are treated with Venclexta/Gazyva have a shorter PFS if they are [IGHV] unmutated, which includes most del(11q) patients, and an even shorter PFS if they have a 

In conclusion, O’Brien stated, “the vast majority of patients with CLL who need therapy will have better outcomes with a BTK inhibitor.”

For more news on cancer updates, research and education, don’t forget to 

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Patients with chronic lymphocytic leukemia should talk to their doctors about the use of BTK inhibitors, as they produced promising outcomes in multiple trials.

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The Facebook conversation drew the attention of Dan Gottlieb, Ph.D., a psychologist who hosts a long-running show on WHYY radio in Philadelphia. He did a segment July 31 in which he helped explain why people say such ridiculous things to those with cancer.

“We are hard-wired to be wary when something looks different,” Gottlieb said. “We are hard-wired be reactive when we are at risk of something.”

Our evolution, he said, makes us anxious in unfamiliar situations, and we instinctively try to assess whether we, ourselves, are at risk.

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If you do want to say something, just ask whether you can help, and how. However, “I would encourage everyone to be aware that you don’t have to say something,” Gottlieb advised.

“If you care, just care,” he said. “Often, you don’t even need words. But a touch on the shoulder —  my God &mdash; that feels so good.”

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BTK Inhibitors Are the Path Forward in Frontline CLL Treatment

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