Early discontinuation of ibrutinib for CLL prevalent in real-world treatment setting
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ORLANDO — Although ibrutinib has been increasingly used for the first-line treatment of chronic lymphocytic leukemia in the community setting, early discontinuation of the agent appeared more prevalent in real-world practice than on clinical trials, according to results of a retrospective cohort study presented at ASH Annual Meeting and Exposition.
“Modern cancer care is increasingly complex, and CLL is one disease which has had dramatic changes in both the diagnostic and treatment landscape in the last 10 years,” Scott F. Huntington, MD, MPH, assistant professor of medicine at Yale School of Medicine and medical oncologist at Smilow Cancer Hospital, said during his presentation. “This also is a disease of the elderly, with a median age at diagnosis of around 71 years, so there are a lot of comorbidities in our patients. The complexity and unique side effects of novel therapies can hinder the translation of recent CLL advancements into routine clinical practice.”
Ibrutinib (Imbruvica; Pharmacyclics, Janssen) — a Bruton tyrosine kinase inhibitor — received FDA approval for relapsed disease in 2014, but since has been shown to be effective in the first-line setting in several pivotal trials. In those trials, ibrutinib appeared well-tolerated, with only 9% of patients discontinuing treatment at 12 months.
“Ibrutinib in the real world, we recognize, has greater toxicities that are common and dissimilar from those associated with cytotoxic chemotherapy,” Huntington said. “The optimal management and supportive care strategies are not well-defined. There is growing evidence that treatment-related toxicities frequently lead to ibrutinib discontinuation outside of clinical trials.”
Huntington and colleagues used the Flatiron Health database to compare early discontinuation rates of ibrutinib in those clinical trials with those observed in a real-world setting, and to determine whether discontinuation was more common among older adults and those with poor performance status, who may have been underrepresented in the trials. Researchers defined early discontinuation as occurring within 180 days of initiation.
The analysis included data from 5,634 patients (median age, 72 years) who initiated first-line CLL therapy between March 1, 2014, and Feb. 28, 2019. From that patient population, researchers assessed trends of first-line ibrutinib use among 5,251 patients who received at least 1 day of treatment, and they assessed ibrutinib discontinuation among 1,496 patients who specifically received ibrutinib for at least 1 day.
Most patients in the cohort (75.8%) had Medicare. More than half of the cohort (60.4%) did not have deletion of 17p, whereas 8.2% harbored the deletion and 31.4% had unknown status.
Researchers noted that the use of ibrutinib increased over time, from approximately 17% of regimens in early 2014 to 45% by late 2018 (P < .001).
Factors associated with greater odds of using ibrutinib include black race (OR = 1.46; 95% CI, 1.13-1.9) and greater years from CLL diagnosis (1 to 3 years, OR = 1.49; 95% CI, 1.22-1.84; 3 to 5 years, OR = 1.91; 95% CI, 1.53-2.39; 5 or more years, OR = 2.57; 95% CI, 2.16-3.06).
Among patients who received ibrutinib, 16.2% discontinued the drug early, with those aged 80 years or older (26.2% vs. 12.5% of those aged younger than 80 years) and those with a worse ECOG performance status ( 2 vs. 0; 33.8% vs. 12.7%; P < .001 for both) more likely to discontinue treatment. Comparatively, 8.3% of patients discontinued ibrutinib within 1 year in a data set of pooled first-line clinical trials.
Multivariable analyses confirmed these associations, with patients aged older than 80 years (OR = 2.3; 95% CI, 1.02-5.2) and those with an ECOG performance status of 2 to 4 (OR = 3.45; 95% CI, 2.16-5.51) more likely to discontinue ibrutinib within 180 days.
Researchers noted that they had incomplete data on noncancer-related medications and comorbidities, and they did not have data on reasons for ibrutinib discontinuation, which limited these findings.
“As part of our next steps, we plan to evaluate provider-level factors associated with early discontinuation, such as CLL experience or volume,” Huntington said. “We’re also looking at supportive care practices that might be associated with discontinuation. Ultimately, we hope to develop and refine an approach that leverages ‘big-data’ and health IT to aid the delivery of modern cancer care.” – by Alexandra Todak
Reference:
Huntington SF, et al. Abstract 797. Presented at: ASH Annual Meeting and Exposition; Dec 7-10, 2019; Orlando.
Disclosures: Huntington reports consultant roles with or honoraria or research funding from AbbVie, Bayer, Celgene, DTRM BioPharma, Genentech and Pharmacyclics. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
Back to TopJames Gerson, MD
These results showing higher ibrutinib discontinuation rates in the community oncology setting compared with pivotal clinical trials are not surprising, because I see this all the time in my own practice. A lot of the clinical trials don’t follow patients as long as practitioners do. Thus, in my practice, even though I have a generally younger, less sick population, discontinuation rates are very high long-term.
These data confirm that discontinuation rates are quite high, especially among the elderly population. The number of patients in this study was obviously quite important, with close to 1,500 patients on ibrutinib. This is a huge data set and representative of a real-world setting, confirming what we’re all seeing in practice.
However, it is hard to interpret these large database studies because they don’t show why patients discontinued treatment. Having the reason for discontinuation — whether it was a specific adverse event, the cost or clinician decision — would be helpful. This limitation puts a little bit of a caveat to the interpretation, but otherwise the results definitely reflect what I see in practice.
Regarding whether early discontinuation affects outcomes — when we look at chronic myeloid leukemia, it’s well-established that a lot of patients can successfully discontinue their TKIs; however, CLL seems completely different. The vast majority of patients are not minimal residual disease negative even with ongoing, prolonged treatment, and so when they stop, they almost always relapse. After stopping treatment, a month later their white count starts nudging up and by 2 months, it is even higher. It’s not necessarily an emergency, but it portends that they are going to need treatment again soon, so most patients who discontinue, especially for an adverse event, will have to go on to subsequent therapy.
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