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Clinically indicated ibrutinib interruptions do not limit long-term benefit in CLL
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Clinically indicated dose reductions or interruptions of ibrutinib did not appear to impact long-term outcomes among patients with chronic lymphocytic leukemia, according to results of a phase 2 prospective study published in Blood.
Ibrutinib (Imbruvica; Pharmacyclics, Janssen), a Bruton tyrosine kinase inhibitor, is FDA approved for all lines of therapy in CLL. Dose modifications or interruptions commonly occur because of adverse events or before invasive procedures.
Researchers sought to examine whether these dose interruptions limit the long-term benefits of the drug.
“Most of the dose interruptions and reductions in our study were done for medically indicated reasons per the FDA label for ibrutinib, not because patients were forgetful, noncompliant or just wanted to take less drug,” Inhye E. Ahn, MD, oncologist at NIH’s NHLBI, told HemOnc Today. “My take from our data is that there are more important biological mechanisms leading to drug resistance, rather than simple drug interruptions or dose reductions.”
Ahn and colleagues analyzed 84 patients with previously untreated CLL (n = 52) or relapsed/refractory CLL (n = 32).
Eligible patients had either a TP53 aberration (n = 53) or were aged older than 65 years (n = 31).
Investigators based dose-interruption data on documented patient history, with each dose-reduction event confirmed on a review of electronic pharmacy orders and patients reporting any missed doses at each clinic visit. Specifically, ibrutinib was held for elective procedures or if grade 3 or higher adverse events occurred.
The effect of dose intensity on PFS and OS served as the study’s primary endpoints.
At a median follow-up of 5.1 years, 75 patients (89.3%) missed at least one ibrutinib dose, and 12 (14.3%) required a permanent dose reduction from full-dose ibrutinib (420 mg daily) to 280 mg daily (n = 10) or 140 mg daily (n = 2). Mean dose intensity was 94.4% (range, 55.3-100).
The most common reasons for treatment breaks included elective procedures (n = 152), adverse events (n = 70) and noncompliance (n = 68).
More than half of patients (n = 57) missed ibrutinib for eight or more consecutive days, whereas 40 missed it for 15 or more consecutive days.
In total, 23 patients experienced disease progression and 18 patients died, including 13 of disease progression.
The mean dose intensity of patients who progressed was 97.7% (range, 88.4-100).
Researchers estimated 5-year PFS of 64.6% (95% CI, 54.6-76.5) for all patients and 72.1% (95% CI, 60.7-85.7) for those who missed an ibrutinib dose for 8 or more consecutive days. Corresponding rates of 5-year OS were 79.6% (95% CI, 71.1-89.1) and 90.1% (95% CI, 82.2-98.8).
Ahn and colleagues noted the high dose intensity in the study and cautioned that the findings should not be extended to general ibrutinib noncompliance.
“Stopping ibrutinib is a huge deal, particularly in patients who have genetic mechanisms of resistance,” Ahn told HemOnc Today. “I discourage holding or dose-reducing ibrutinib without having medically indicated reasons to justify continuous, full-dose therapy.” – by John DeRosier
For more information:
Inhye E. Ahn , MD , can be reached at NHLBI, Building 31, 31 Center Drive., Bethesda MD, 20892; email: nhye.ahn@nih.gov.
Disclosures: Pharmacyclics funded this study. Ahn reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
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Ahn IE, et al. Blood. 2019;doi:10.1182/blood.2019896688.
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