Real-World Findings for Ibrutinib in Patients With CLL: Toxicities, Discontinuations, and More

December 10, 2017

Ibrutinib is approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL).

Researchers sought to study real-world outcomes related to adverse events (AEs), treatment discontinuation, outcomes, and subsequent therapies in those treated with frontline ibrutinib. Anthony R. Mato, MD, at the University of Pennsylvania Abramson Cancer Center in Philadelphia, PA, discussed the findings at the ASH Annual Meeting (

The researchers performed a retrospective cohort analysis of 391 patients (median age = 68 years, range = 36–96) with CLL who were treated with frontline ibrutinib at 19 U.S. and international academic and community sites. Most patients (92%) were Caucasian, and patient mutations included del(17p) (30%), del(11q) (17%), TP53 (20%), complex karyotype (at least three abnormalities; 23%), and unmutated immunoglobulin heavy-chain variable (IGHV; 67%). Fifty-seven patients (14.5%) were genetically low risk. Seventy-six percent of patients underwent fluorescence in situ hybridization testing, and of the 79 patients with complete data, CLL-International Prognostic Index risk classifications were low risk (2.5%), intermediate risk (20%), high risk (49.5%), and very high risk (28%).

They collected data on demographics, clinical-molecular-genetic prognostic factors, dosing, discontinuation rate and reasons, AEs, overall response rates (ORRs), complete responses (CRs), and survival outcomes. Subsequent treatments following ibrutinib discontinuation, sequencing, and outcomes associated with subsequent therapies were assessed.

The median time from CLL diagnosis to the start of ibrutinib therapy was 31 months (range = 0–336). Eight percent of patients received initial doses of less than 420 mg daily, whereas 16% received ibrutinib combination, with anti-CD20 therapy being the most common pair (95%). Seventeen percent of patients required a permanent dose reduction (median continued dose = 280 mg), and 42% required a dose interruption (median time off ibrutinib = 12 days).

ORR was 81.7%, including a 17.4% CR rate. After a median follow up of 14 months, the median progression-free survival ([PFS], primary endpoint) and overall survival (OS) had not been reached. Twelve-month PFS and OS rates were 92% and 95%, respectively. In patients with del(17p), 12-month PFS and OS rates were 87% and 89%, respectively.

A univariate analysis assessed the impact on PFS for the following: at least 65 years old, sex, del(17p), del(11q), TP53, complex karyotype, IGHV status, lactate dehydrogenase, and β2-microglobulin. Only del(17p) was associated with inferior PFS (odds ratio = 1.91, 95% CI = 1.04–3.51, p = 0.037).

Twenty-four percent of patients (n = 94) discontinued ibrutinib after a median of 6.5 months (range = 0.1–41). Toxicity was the most common reason for discontinuation (59.5%), with the most common AEs associated with discontinuation being atrial fibrillation (20%), arthralgia or myalgia (14.5%), dermatologic issues (14.5%), and bleeding (9.1%).

The most common any-grade AEs associated with ibrutinib included arthralgia or myalgia (21.2%), fatigue (18.7%), dermatologic issues (17.9%), bruising (17.9%), diarrhea or colitis (17.4%), infection (14.8%), and bleeding (13.2%).

Fourteen percent of patients (n = 55) required subsequent therapy, the three most common of which were anti-CD20 with or without chlorambucil (32.6%, ORR = 58%), venetoclax (18%, ORR = 89%), and alternate kinase inhibitor (12.6%, ORR = 40%). “Interestingly, many patients did not require immediate treatment following discontinuation, suggesting sustained responses,” the researchers reported.

At the time of the analysis, the combined ORR following ibrutinib discontinuation on all subsequent therapies was 61%, and 69% of patients have not experienced disease progression.

“PFS and OS in this high-risk population is comparable to earlier studies [of the drug], but patients are more likely to have dose reductions, [dose] interruption, and initiate therapy at lower than the FDA-approved dose,” the researchers concluded.

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