Do Low- and Moderate-Grade Adverse Events Affect Rates of Treatment Discontinuation in CLL?

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In an analysis from the phase III ECOG/ACRIN E1912 trial in chronic lymphocytic leukemia (CLL) published in the Journal of Clinical Oncology, O’Connell et al found that grade 1 and 2 adverse events were significant contributors to patient-reported side-effects bother, with grade 2 events being associated with increased odds of treatment discontinuation.  

Study Details

In the trial, patients with CLL received 28-day cycles of continuous ibrutinib or six 28-day cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab on days 1 to 3. The Functional Assessment of Cancer Therapy–GP5 item, “I am bothered by side effects of treatment,” was used to define side-effect bother using a five-item scale.   

Key Findings

Among all adverse events reported in the trial, 70.5% were grade 1, 19.9% were grade 2, 8.0% were grade 3, 1.6% were grade 4, and < 0.1% were grade 5. Each additional grade 1 adverse event occurring during a treatment cycle increased the odds of increased self-reported patient side-effect bother by 13% (odds ratio [OR] = 1.13, 95% credible interval [CrI] = 1.06–1.21). Each additional grade 2 adverse event during a treatment cycle increased odds of increased self-reported bother by 35% (OR = 1.35, 95% CrI = 1.19–1.54).  

Increased odds of increased side-effect bother were observed for symptomatic grade 1 adverse events (OR = 1.37, 95% CrI = 1.24–1.52) but not asymptomatic grade 1 adverse events (OR = 0.89, 95% CrI = 0.79–1.00). Increased odds were also observed for symptomatic (OR = 2.06, 95% CrI = 1.60–2.64) but not asymptomatic grade 2 adverse events (OR = 1.06, 95% CrI = 0.89–1.26).

Each additional grade 1 adverse event was associated with an 11% decreased odds of treatment discontinuation (OR = 0.89, 95% CrI = 0.78–1.00), with odds ratios of 0.89 (95% CrI = 0.73–1.07) for symptomatic events and 0.94 (95% CrI = 0.76–1.13) for asymptomatic events.

Each additional grade 2 adverse event was associated with a 59% increased odds of treatment discontinuation (OR = 1.59, 95% CrI = 1.32–1.95). The association with treatment discontinuation was stronger for symptomatic (OR = 1.75, 95% CrI = 1.28–2.39) vs asymptomatic events (OR = 1.45, 95% CrI = 1.12–1.89), according to the study authors.

The investigators concluded: “Low- and moderate-grade adverse events are related to increased odds of increased patient side-effect bother and treatment discontinuation, with symptomatic adverse events demonstrating greater magnitude of association than asymptomatic. Our findings suggest that limiting adverse event capture to grade 3 [or higher] misses important contributors to treatment side-effect bother and discontinuation.”

Nathaniel S. O’Connell, PhD, of the Department of Biostatistics and Data Science, Wake Forest University School of Medicine, is the corresponding author of the Journal of Clinical Oncology article.

Disclosure: The study was funded by the National Cancer Institute. For full disclosures of the study authors, visit

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